Variant classification summary

NM_000215.3:c.1531A>G

JAK3 · NP_000206.2:p.(Met511Val) · NM_000215.3

GRCh37: chr19:17949110 T>C · GRCh38: chr19:17838301 T>C

Gene: JAK3 Transcript: NM_000215.3

Final call

VUS

PM2 supporting

Variant details

Gene

JAK3

Transcript

NM_000215.3

Protein

NP_000206.2:p.(Met511Val)

gnomAD AF

6.195717767707671e-06 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000215.3:c.1531A>G (p.Met511Val) is a missense variant in exon 11 of JAK3 affecting the pseudokinase domain.

2

This variant is extremely rare in population databases, with a popmax filtering allele frequency of 8.79e-06 in gnomAD v2.1 and 8.47e-06 in v4.1 (European non-Finnish), and zero homozygotes observed, meeting PM2_Supporting per SCID VCEP specifications (threshold <0.000115).

3

The variant is absent from ClinVar, COSMIC, and gnomAD-Canada.

4

No variant-specific functional evidence is available. The SCID VCEP-approved PS3_Supporting in vitro kinase assay (PMID:14615376) tested other JAK3 variants but not M511V. The related M511I variant has been characterized in a somatic T-ALL context (PMID:25193870) but these findings cannot be directly extrapolated to germline M511V in SCID.

5

No de novo observations, segregation data, or patient phenotype information is available. PM1 does not apply because M511 is not one of the two specified JH2 domain residues (R651, C759).

6

Based on SCID VCEP v2.3.0 criteria, the only applicable criterion met is PM2_Supporting. This is insufficient for classification as Likely Pathogenic or Pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is reserved for null/loss-of-function variants (nonsense, frameshift, canonical splice). NM_000215.3:c.1531A>G is a missense variant (p.Met511Val) and does not qualify.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic or likely pathogenic variant at the same nucleotide position (c.1531) in JAK3 classified by SCID VCEP specifications.	cspec
PS2	Not met	No de novo observation reported for this variant in any available source.	cspec
PS3	Not met	No variant-specific functional evidence available. The SCID VCEP-approved PS3_Supporting assay (in vitro kinase assay, PMID:14615376) tested c.266_268del, c.602C>A, and c.1860G>A — not this variant. PMID:25193870 studied JAK3 M511I in a somatic T-ALL context, not M511V.	cspec vcep_scid_vcep_ps3_bs3_functional_evidence_jak3 PMID:25193870
PS4	N/A	PS4 is not applicable per SCID VCEP specifications for JAK3.	cspec
PS5	N/A	PS5 is not a criterion used by the SCID VCEP specifications for JAK3 (analogous to PP5 which is explicitly Not Applicable).	cspec
PM1	Not met	PM1 is defined by the SCID VCEP to include only missense alterations of two specific JH2 pseudokinase domain residues: R651W and C759R (PMID:11668610). M511V is located at a different residue and does not qualify.	cspec
PM2	Met	This variant is extremely rare in gnomAD (popmax filtering allele frequency 8.79e-06 in European non-Finnish, v2.1; 8.47e-06 in v4.1), well below the SCID VCEP PM2_Supporting threshold of 0.000115, with zero homozygotes observed.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No previously established pathogenic missense variant at residue 511 classified by SCID VCEP specifications. M511I has been studied in a somatic T-ALL context (PMID:25193870) but lacks a germline SCID VCEP classification and is a different amino acid change.	cspec pm5_candidates
PM6	Not met	No de novo observation reported for this variant. The variant is absent from ClinVar and no de novo report was identified in the publication corpus.	cspec
PP1	Not met	No co-segregation data available for this variant in any source.	cspec
PP2	N/A	PP2 is not applicable per SCID VCEP specifications for JAK3.	cspec
PP3	N/A	Per SCID VCEP, PP3 may only be applied to synonymous or intronic variants predicted to impact splicing (SpliceAI delta ≥0.2). This is a missense variant; PP3 is not applicable.	cspec
PP4	Not assessed	No patient phenotype information is available to calculate the SCID VCEP PP4 patient score (requires diagnostic criteria, gene panel/sequencing results, phosphorylation data, gene therapy confirmation, or lymphocyte subset profile).	cspec vcep_jak3_pp4
PP5	N/A	PP5 is not applicable per SCID VCEP specifications for JAK3.	cspec
BA1	Not met	Popmax filtering allele frequency in gnomAD (8.79e-06) is well below the SCID VCEP BA1 Stand Alone threshold of >0.00447.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Popmax filtering allele frequency in gnomAD (8.79e-06) is below the SCID VCEP BS1 threshold of >0.00100.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No homozygotes have been observed in gnomAD (v2.1: 0 hom; v4.1: 0 hom). SCID VCEP requires at least 1 homozygote in a healthy adult for BS2_Supporting.	gnomad_v2 gnomad_v4 cspec
BS3	N/A	BS3 is not applicable per SCID VCEP specifications for JAK3.	cspec
BS4	Not met	No segregation data available to demonstrate lack of co-segregation with disease. BS4 requires observation that the variant does not segregate with the SCID phenotype in affected families.	cspec
BP1	N/A	BP1 is not applicable per SCID VCEP specifications for JAK3.	cspec
BP2	N/A	BP2 is not applicable per SCID VCEP specifications for JAK3.	cspec
BP3	N/A	BP3 applies to in-frame indels in repetitive regions. This is a single nucleotide substitution, not an indel.
BP4	N/A	BP4 is not applicable per SCID VCEP specifications for JAK3.	cspec
BP5	N/A	BP5 is not applicable per SCID VCEP specifications for JAK3.	cspec
BP6	N/A	BP6 is not applicable per SCID VCEP specifications for JAK3.	cspec
BP7	N/A	BP7 applies only to synonymous variants and deep intronic variants at or beyond +7 (donor) and -21 (acceptor) positions. This is a missense variant and does not qualify.	cspec

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