Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000215.4(JAK3):c.394C>A (p.Pro132Thr)

CA160246

134580 (ClinVar)

Gene: JAK3

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

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9575ceca-8501-4b6e-9c16-23e270b5e961

HGVS expressions

NM_000215.4:c.394C>A

NM_000215.4(JAK3):c.394C>A (p.Pro132Thr)

NC_000019.10:g.17843406G>T

CM000681.2:g.17843406G>T

NC_000019.9:g.17954215G>T

CM000681.1:g.17954215G>T

NC_000019.8:g.17815215G>T

NG_007273.1:g.9586C>A

ENST00000458235.7:c.394C>A

ENST00000458235.5:c.394C>A

ENST00000526008.5:n.494C>A

ENST00000527031.5:n.484C>A

ENST00000527670.5:c.394C>A

ENST00000528293.1:n.409C>A

ENST00000534444.1:c.394C>A

NM_000215.3:c.394C>A

Benign

BA1 BS2_Supporting

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr). The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria. In summary, this variant meets the criteria to be classified as Benign 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. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0).

BA1

The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1).

BS2_Supporting

Furthermore, 321 adult homozygous were described in GnomAD v.4, meeting BS2_Supporting criteria.

Approved on: 2024-01-23

Published on: 2024-01-23

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