NM_002227.3:c.1909G>A

JAK1 · NP_002218.2:p.(Glu637Lys) · NM_002227.3

GRCh37: chr1:65312410 C>T · GRCh38: chr1:64846727 C>T

Gene: JAK1 Transcript: NM_002227.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

JAK1

Transcript

NM_002227.3

Protein

NP_002218.2:p.(Glu637Lys)

gnomAD AF

1.2393600935964742e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002227.3:c.1909G>A (p.Glu637Lys) is extremely rare in population databases, present in gnomAD v4.1 at an allele frequency of 1.24e-06 (2/1,613,736 alleles, 0 homozygotes) and absent from gnomAD v2.1 and gnomAD-Canada v1.0. This meets PM2 at the supporting level.

Computational evidence supports a deleterious effect: REVEL predicts a damaging score of 0.762, meeting PP3 at the supporting level under generic ACMG/AMP guidelines. SpliceAI predicts no splicing impact (max delta=0.00).

This variant is a missense substitution (p.Glu637Lys) and does not meet PVS1 null-variant criteria. No functional studies, segregation data, de novo observations, case-control data, or prior clinical classifications are available. The variant has been reported in COSMIC (COSV61089427, n=2) in a somatic context but lacks germline disease association evidence.

Only two supporting-level pathogenic criteria are met (PM2_supporting, PP3_supporting). No moderate, strong, or very strong pathogenic criteria are met. No benign criteria are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting criteria are insufficient to reach Likely Pathogenic (minimum: 1 strong + 2 supporting, or 2 moderate + 2 supporting, or 3 moderate, etc.). The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_002227.3:c.1909G>A is a missense substitution (p.Glu637Lys). It does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). PVS1 is not applicable to missense variants under the generic ACMG/AMP framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No evidence was identified of a different nucleotide change at the same codon producing the same missense change (p.Glu637Lys). PS1 cannot be assessed without a known pathogenic comparator variant at this residue arising from a different nucleotide substitution.
PS2	Not assessed	No de novo data are available for NM_002227.3:c.1909G>A. No publications or database entries report de novo occurrence of this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for NM_002227.3:c.1909G>A. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data comparing affected individuals to general population controls are available for this variant. Reported in COSMIC (COSV61089427, n=2) in a somatic cancer context, but this does not constitute germline PS4 evidence.
PS5	Not assessed	No reputable source (e.g., clinical diagnostic laboratory, ClinGen expert panel) has classified NM_002227.3:c.1909G>A as pathogenic. This variant is absent from ClinVar entirely.	clinvar
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot in JAK1. Residue Glu637 is not identified as a recurrently altered position in cancer or germline disease.
PM2	Met	NM_002227.3:c.1909G>A is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF=1.24e-06, 2/1,613,736 alleles, 0 homozygotes). The highest subpopulation frequency is in the Remaining individuals group (AF=1.6e-05, 1/62,500 alleles). Absent from gnomAD-Canada v1.0. This allele frequency is well below the 0.1% PM2 threshold for a rare variant, supporting a moderately deleterious interpretation at the supporting level under generic ACMG/AMP.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variant could be identified for codon 637 of JAK1. The automated PM5 candidate search returned zero candidates. Unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not assessed	No de novo data are available for NM_002227.3:c.1909G>A. No publications or database entries report de novo occurrence.
PP1	Not assessed	No co-segregation data are available for NM_002227.3:c.1909G>A. No family studies with segregation analysis have been reported.
PP2	Not assessed	Insufficient gene-level constraint data are available for JAK1 to determine whether missense variants are a common mechanism of disease with a low rate of benign missense variation. JAK1 is not present in the HCI prior database, and no gnomAD constraint metrics (Z-score, pLI, missense o/e) were retrieved for formal PP2 assessment.
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL predicts a damaging score of 0.762 (above the 0.5 threshold commonly used for PP3_supporting). SpliceAI predicts no splice impact (max delta=0.00), which is expected for a missense substitution distant from splice junctions. BayesDel (0.268) is below typical deleterious thresholds, but REVEL, as an ensemble method incorporating multiple predictors, provides sufficient in silico support at the supporting level under generic ACMG/AMP.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for this case. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease in question, which cannot be evaluated without clinical information.
PP5	Not assessed	No reputable source has classified NM_002227.3:c.1909G>A as pathogenic. The variant is absent from ClinVar and has not been reported as pathogenic by any clinical diagnostic laboratory.	clinvar
BA1	Not met	The allele frequency of NM_002227.3:c.1909G>A (AF=1.24e-06 in gnomAD v4.1) is far below the 1% BA1 threshold. This variant is not a common polymorphism.	gnomad_v4
BS1	Not met	The allele frequency of NM_002227.3:c.1909G>A (AF=1.24e-06, 0.00012%) is far below the 0.3% BS1 threshold. This variant is too rare to meet BS1.	gnomad_v4
BS2	Not assessed	No data are available regarding observation of NM_002227.3:c.1909G>A in healthy adults with full penetrance expected at an early age. BS2 requires intact clinical phenotyping of carriers, which is not available from population databases.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of p.Glu637Lys are available. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease. BS4 requires family studies demonstrating absence of segregation, which are not available.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. JAK1 has supporting literature evidence for a loss-of-function disease mechanism in a germline context (familial lung cancer susceptibility), and missense variants are a plausible disease mechanism for this kinase. BP1 is not applicable.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation of NM_002227.3:c.1909G>A in trans with a known pathogenic JAK1 variant. BP2 cannot be assessed without phase information.
BP4	Not met	Computational evidence does not support a benign interpretation. REVEL predicts a deleterious score of 0.762. While BayesDel (0.268) is lower and SpliceAI shows no splicing impact (max delta=0.00), the ensemble REVEL score provides evidence against a benign classification. BP4 requires multiple lines of computational evidence suggesting no impact, which is not satisfied.	revel bayesdel spliceai
BP5	Not assessed	No alternative molecular cause for disease has been identified in this case. BP5 requires that a pathogenic variant in an alternative gene was found, which is not applicable without additional clinical data.
BP6	Not assessed	No reputable source has classified NM_002227.3:c.1909G>A as benign. The variant is absent from ClinVar and has no prior benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_002227.3:c.1909G>A is a missense variant (p.Glu637Lys), not a synonymous variant. BP7 is not applicable.

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