Variant: NM_001369369.1(FOXN1):c.1135+20G>A

CA8459444

1127854 (ClinVar)

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: 69b404c6-a68c-4586-972b-fffa31853d5d

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.1135+20G>A
NM_001369369.1(FOXN1):c.1135+20G>A
NC_000017.11:g.28534558G>A
CM000679.2:g.28534558G>A
NC_000017.10:g.26861576G>A
CM000679.1:g.26861576G>A
NC_000017.9:g.23885703G>A
NG_007260.1:g.15618G>A
ENST00000577936.2:c.1135+20G>A
ENST00000579795.6:c.1135+20G>A
ENST00000226247.2:c.1135+20G>A
ENST00000481916.6:c.*1195+69493C>T
ENST00000579795.5:c.1135+20G>A
NM_003593.2:c.1135+20G>A
NM_003593.3:c.1135+20G>A

Likely Benign

• Met criteria codes: BP4 BP7

• Not Met criteria codes: BS1 PM2

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

NM_001369369.1(FOXN1):c.1135+20G>A is an intronic variant. SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (delta scores 0.00) and the nucleotide is not highly conserved (phyloP score -0.235) (BP4, BP7). In summary this variant meets criteria to be classified as likely benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BP4 and BP7 as specified by the ClinGen SCID VCEP FOXN1 subgroup.

Met criteria codes

• BP4: SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (delta scores 0.00).
• BP7: SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (delta scores 0.00) and the nucleotide is not highly conserved (phyloP score -0.235).

Not Met criteria codes

• BS1: The variant occurs at an allele frequency between the BS1 (>0.00141) and PM2 (<0.00002412) thresholds, with a gnomADv4.0 GrpMax filtering AF of 0.001095 based on 1352/1179186 alleles in the European (non-Finnish) population. Note the Middle Eastern population has a MAF of 0.002502 but that is not considered for BS1 due to the higher incidence of SCID in this bottle-necked population.
• PM2: The variant occurs at an allele frequency between the BS1 (>0.00141) and PM2 (<0.00002412) thresholds, with a gnomADv4.0 GrpMax filtering AF of 0.001095 based on 1352/1179186 alleles in the European (non-Finnish) population. Additionally a homozygote is present in the Admixed American population.