Variant: NM_000215.4(JAK3):c.1915-1G>A

CA404768497

2048620 (ClinVar)

Gene: JAK3

Condition: T-B+ severe combined immunodeficiency due to JAK3 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 60dd60ca-5596-48cc-81d5-5dad6eee4047

HGVS expressions

NM_000215.4:c.1915-1G>A
NM_000215.4(JAK3):c.1915-1G>A
NC_000019.10:g.17835216C>T
CM000681.2:g.17835216C>T
NC_000019.9:g.17946025C>T
CM000681.1:g.17946025C>T
NC_000019.8:g.17807025C>T
NG_007273.1:g.17776G>A
ENST00000458235.7:c.1915-1G>A
ENST00000458235.5:c.1915-1G>A
ENST00000527031.5:n.2278+1511G>A
ENST00000527670.5:c.1915-1G>A
ENST00000534444.1:c.1915-1G>A
NM_000215.3:c.1915-1G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: PVS1

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 JAK3 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The variant NM_000215.4(JAK3):c.1915-1G>A is predicted to disrupt an acceptor splice site in intron 14; however, this variant falls into a NAGNAG sequence, which may indicate a frame restoring splice site (PVS1 not met). The variant has an allele frequency that is too low to calculate a popmax allele frequency accurately; there is a single heterozygous case (1/112366 alleles or MAF of 0.000008899 in the European non-Finnish population), and no homozygous cases were reported in gnomAD v2.1.1. This is below the SCID VCEP threshold of <0.000115 (PM2_supporting). To our knowledge, the variant has not been reported in the literature in any individuals with JAK3 deficiency. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting. (SCID VCEP Specification Version 1).

Met criteria codes

• PM2_Supporting: The variant has an allele frequency that is too low to calculate a popmax allele frequency and thus meets PM2_supporting. There is a single heterozygous case (1/112366 alleles or MAF of 0.000008899 in the European non-Finnish population) and no homozygous cases were reported in gnomAD v2.1.1. This is below the SCID VCEP threshold of <0.000115 (PM2_supporting).

Not Met criteria codes

• PVS1: The variant NM_000215.4(JAK3):c.1915-1G>A is predicted to disrupt an acceptor splice site in intron 14, however this variant falls into a NAGNAG sequence, which may indicate a frame restoring splice site.

Approved on: 2024-01-17

Published on: 2024-01-17