Variant: NM_001369369.1(FOXN1):c.962A>G (p.His321Arg)

CA16607552

392379 (ClinVar)

Gene: FOXN1

Condition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Inheritance Mode: Semidominant inheritance

UUID: 7ca8661b-1f2e-4d0c-882f-bfe8a40261db

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.962A>G
NM_001369369.1(FOXN1):c.962A>G (p.His321Arg)
NC_000017.11:g.28534365A>G
CM000679.2:g.28534365A>G
NC_000017.10:g.26861383A>G
CM000679.1:g.26861383A>G
NC_000017.9:g.23885510A>G
NG_007260.1:g.15425A>G
ENST00000577936.2:c.962A>G
ENST00000579795.6:c.962A>G
ENST00000226247.2:c.962A>G
ENST00000481916.6:c.*1195+69686T>C
ENST00000579795.5:c.962A>G
NM_003593.2:c.962A>G
NM_003593.3:c.962A>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4 PM1 PP3_Moderate

• Not Met criteria codes: PM5 PS3

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXN1 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_001369369.1(FOXN1):c.962A>G (p.His321Arg) missense variant is located within the well-established DNA binding forkhead domain (amino acids 270-367) at amino acid position 321 (PM1). A deleterious effect is predicted by REVEL with a score of 0.978, above the ≥0.932 threshold for PP3_moderate. This variant was detected heterozygous by exome sequencing in P7 (PMID: 31566583) with T lymphopenia (CD3 32 cell/ul), abnormal hair and abnormal nails (PP4), This variant has a HMAF of 0.000002856 (1/350108 alleles) in the European (non-Finnish) population of gnomADv4.0, below the threshold of <0.00002412 (PM2_supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PP3_moderate, PM1, PM2_supporting, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup.

Met criteria codes

• PM2_Supporting: This variant has a HMAF of 0.000002856 (1/350108 alleles) in the European (non-Finnish) population of gnomADv4.0, below the threshold of <0.00002412 (PM2_supporting).
• PP4: P7 (PMID: 31566583) at 8 days old cells counts in cells/uL were: CD3 32 (2500–5600) (0.5pt), CD4 13 (1900–5900), CD8 9 (1040–1700), CD4,CD45RA 1 (1100–3700), NK 105 (160–950), CD19+ 1280 (610–2600). Reported to have abnormal hair and nails with no further detail. Variant was detected by exome sequencing (0.5pt). Total 1pt
• PM1: The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 321, and thus meets PM1.
• PP3_Moderate: A deleterious effect is predicted by REVEL with a score of 0.978, above the ≥0.932 threshold for PP3_moderate.

Not Met criteria codes

• PM5: Two additional variants have been reported at this codon, His321Tyr and His321Asn, but have not yet been curated by the SCID VCEP. Use of PM5 would not affect the classification so has not been considered at this time.
• PS3: Expression vectors containing Foxn1 variants were transfected into HeLa cells along with the β5t-luciferase reporter construct, a well-defined transcriptional target of Foxn1. This variant resulted in 206% activity in the reporter assay compared to WT (PMID: 37419334). Not considered here as the GOF mechanism is not well established and the assay has not been validated for GOF.