About JAK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
JAK1 c.1909G>A, p.(Glu637Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,613,736 alleles
gnomAD v4.1: 2 / 1,613,736 alleles. Recorded AF 1.23936e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. JAK1, an intracellular kinase, is frequently altered in hematologic malignancies and gynecological cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61089427, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 4 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=1.24e-06 (2/1
- 613
- 736 alleles
- 0 homozygotes)
- gnomAD-Canada v1.0: absent
Sources
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.762 (deleterious prediction)
- BayesDel score: 0.268 (below typical deleterious threshold)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
Not met · 4 · evaluated, threshold not reached
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots analysis: residue not statistically significant
- exact variant not listed.
BA1 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. Details ▾Hide ▴
BS1 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. Details ▾Hide ▴
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.762 (predicts deleterious
- contradicting BP4)
- BayesDel: 0.268
- SpliceAI max delta: 0.00
Sources
Not assessed · 16 · no assessment recorded
PS1 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. Details ▾Hide ▴
Still missing
- No alternate nucleotide change producing p.Glu637Lys identified in ClinVar or literature.
PS2 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. Details ▾Hide ▴
Still missing
- No de novo testing or trio sequencing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB reports no variant-specific reviewed functional evidence for JAK1 E637K.
Still missing
- No functional studies assessing the impact of p.Glu637Lys on JAK1 kinase activity
- signaling
- or protein stability.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- COSMIC reports 2 somatic occurrences
- no germline case-control data available.
Still missing
- No germline case-control or cohort prevalence data for JAK1 c.1909G>A in any disease phenotype.
PM6 No de novo data are available for NM_002227.3:c.1909G>A. No publications or database entries report de novo occurrence. Details ▾Hide ▴
Still missing
- No de novo testing or confirmed de novo observations.
PP1 No co-segregation data are available for NM_002227.3:c.1909G>A. No family studies with segregation analysis have been reported. Details ▾Hide ▴
Still missing
- No family-based segregation analysis available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI prior not available for JAK1
- no gnomAD constraint metrics retrieved.
Still missing
- gnomAD gene constraint metrics (missense Z-score
- o/e) not available for formal PP2 adjudication.
PP4 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. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical history provided for phenotype-specificity assessment.
PP5 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic assertion from any submitter.
Still missing
- No reputable source has classified this variant as pathogenic.
Sources
BS2 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. Details ▾Hide ▴
Still missing
- No clinical phenotyping of the 2 gnomAD v4.1 carriers to confirm healthy adult status.
BS3 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. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign effect identified.
Still missing
- No functional characterization of JAK1 p.Glu637Lys.
Sources
BS4 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. Details ▾Hide ▴
Still missing
- No segregation data to evaluate BS4.
BP2 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. Details ▾Hide ▴
Still missing
- No data on trans configurations with pathogenic JAK1 variants.
BP5 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. Details ▾Hide ▴
Still missing
- No data on alternative molecular diagnoses.
BP6 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign assertion exists.
Still missing
- No reputable source has classified this variant as benign.
Sources
PS5 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. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no prior germline classification exists.
Still missing
- No prior pathogenic classification from any clinical laboratory or expert panel.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Missense variant classified as 'other' bucket under PMC6185798 PVS1 decision tree
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting found no same-residue comparator variants at Glu637.
Sources
pm5_candidates
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
- PVS1 gene context supports LOF as a disease mechanism
- missense variants not excluded as pathogenic in JAK1.
Sources
pvs1_gene_context
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous variants.
Identifiers
- Gene
- JAK1
- Transcript
- NM_002227.3
- Coding (HGVS c.)
- NM_002227.3:c.1909G>A
- Protein (HGVS p.)
- NP_002218.2:p.(Glu637Lys)
- GRCh38
- chr1:64846727 C>T
- GRCh37
- chr1:65312410 C>T
- COSMIC
- COSV61089427
Gene diagram
Every interpreted variant in JAK1, mapped onto the exon structure of NM_002227.3. Select a row to find it on the plot.
JAK1NM_002227.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in JAK1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,613,736 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,736 alleles · 0 hom
| Remaining individuals1 / 62,500 | 1.6e-05 |
| European (non-Finnish)1 / 1,179,796 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23936e-06; MAF= 0.00012%, 2/1613736 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6e-05; MAF= 0.00160%, 1/62500 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.762
- BayesDel
- 0.268
How the predictions were used
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.762 (deleterious prediction)
- BayesDel score: 0.268 (below typical deleterious threshold)
- SpliceAI max delta: 0.00 (no predicted splice impact)
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.762 (predicts deleterious
- contradicting BP4)
- BayesDel: 0.268
- SpliceAI max delta: 0.00
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.762. BayesDel score = 0.267658.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,613,736 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002227.3%3Ac.1909G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-65312410-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-64846727-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-64846727-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002227.3%3Ac.1909…
- OncoKB ↗www.oncokb.org/gene/JAK1/E637K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127371706
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23936e-06; MAF= 0.00012%, 2/1613736 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6e-05; MAF= 0.00160%, 1/62500 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.762. BayesDel score = 0.267658.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. JAK1, an intracellular kinase, is frequently altered in hematologic malignancies and gynecological cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61089427, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.