About JAK3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
JAK3 c.1531A>G, p.(Met511Val)
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 ClinGen JAK3 VCEP v2.3.0. 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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting; no rule matched the adjudicated criteria.
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
10 / 1,614,018 alleles
gnomAD v4.1: 10 / 1,614,018 alleles. Recorded AF 6.19572e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97621e-06; MAF= 0.00040%, 1/251496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78966e-06; MAF= 0.00088%, 1/113770 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.250 maximum delta
Recorded SpliceAI maximum delta score: 0.250. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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. JAK3, a non-receptor tyrosine kinase, is recurrently altered by mutation in hematologic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen JAK3 VCEP v2.3.0, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 11 not met · 1 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000215.3:c.1531A>G (p.Met511Val) is a missense variant in exon 11 of JAK3 affecting the pseudokinase domain.
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).
The variant is absent from ClinVar, COSMIC, and gnomAD-Canada.
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.
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).
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).
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 496 alleles
- popmax nfe AF=8.79e-06
- hom=0
- gnomAD v4.1: 10/1
- 614
- 018 alleles
- popmax nfe AF=8.47e-06
- Absent from gnomAD-Canada v1.0
Sources
Not met · 11 · evaluated, threshold not reached
PS1 No previously established pathogenic or likely pathogenic variant at the same nucleotide position (c.1531) in JAK3 classified by SCID VCEP specifications. Details ▾Hide ▴
Evidence considered
- No known pathogenic variant at c.1531 in JAK3
- ClinVar contains no submissions for this variant or same-nucleotide comparators
Sources
PS2 No de novo observation reported for this variant in any available source. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no de novo report identified in publication corpus
Still missing
- No parental testing data available
Sources
PS3 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. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional assay (PMID:14615376) does not include M511V
- PMID:25193870 tested M511I
- a different amino acid substitution at the same residue but in a somatic cancer context
Still missing
- No germline-relevant functional data for M511V
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- M511V affects residue 511 in the pseudokinase domain
- not one of the two specified PM1 residues (R651
- C759)
Sources
PM5 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. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: no eligible same-residue comparator variants
- M511I is a somatic cancer variant without SCID VCEP classification
Still missing
- No germline-classified comparator at residue 511
Sources
cspec ↗pm5_candidates
PM6 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no de novo reports identified
Still missing
- No parental testing data available
Sources
PP1 No co-segregation data available for this variant in any source. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified for this variant
Still missing
- No segregation or family data available
Sources
BA1 Popmax filtering allele frequency in gnomAD (8.79e-06) is well below the SCID VCEP BA1 Stand Alone threshold of >0.00447. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 popmax nfe AF=8.79e-06
- gnomAD v4.1 popmax nfe AF=8.47e-06
- BA1 threshold: >0.00447
Sources
BS1 Popmax filtering allele frequency in gnomAD (8.79e-06) is below the SCID VCEP BS1 threshold of >0.00100. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 popmax nfe AF=8.79e-06
- gnomAD v4.1 popmax nfe AF=8.47e-06
- BS1 threshold: >0.00100
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- Zero homozygotes observed in gnomAD v2.1 and v4.1
Sources
BS4 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. Details ▾Hide ▴
Evidence considered
- No family or segregation data available
Still missing
- Segregation data from affected families would be needed
Sources
Not assessed · 1 · no assessment recorded
PP4 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). Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical data provided for PP4 scoring
Still missing
- Patient phenotype data needed: SCID diagnostic criteria
- lymphocyte subsets
- phosphorylation assay results
- gene therapy status
Sources
cspec ↗vcep_jak3_pp4
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null/LoF variant type eligible for PVS1 under ClinGen SVI recommendations
Sources
PS4 VCEPPS4 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
PP3 N/APer 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- VCEP restricts PP3 to synonymous/intronic variants only
Sources
PP5 VCEPPP5 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP3 VCEPBP3 applies to in-frame indels in repetitive regions. This is a single nucleotide substitution, not an indel. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 requires in-frame insertion/deletion
BP4 VCEPBP4 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP5 VCEPBP5 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous/deep intronic variants per SCID VCEP
Sources
PS5 N/APS5 is not a criterion used by the SCID VCEP specifications for JAK3 (analogous to PP5 which is explicitly Not Applicable). Details ▾Hide ▴
Evidence considered
- Not part of the SCID VCEP JAK3 criteria set
- PP5 is explicitly Not Applicable
Sources
Identifiers
- Gene
- JAK3
- Transcript
- NM_000215.3
- Coding (HGVS c.)
- NM_000215.3:c.1531A>G
- Protein (HGVS p.)
- NP_000206.2:p.(Met511Val)
- GRCh38
- chr19:17838301 T>C
- GRCh37
- chr19:17949110 T>C
Gene diagram
Every interpreted variant in JAK3, mapped onto the exon structure of NM_000215.3. Select a row to find it on the plot.
JAK3NM_000215.3
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 JAK3
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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
10 / 1,614,018 alleles
AF 6.2e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
1 / 251,496 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-06 · 10 / 1,614,018 alleles · 0 hom · FAF 4.3e-06
| European (non-Finnish)10 / 1,180,036 | 8.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,496 alleles · 0 hom
| European (non-Finnish)1 / 113,770 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19572e-06; MAF= 0.00062%, 10/1614018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-06; MAF= 0.00085%, 10/1180036 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97621e-06; MAF= 0.00040%, 1/251496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78966e-06; MAF= 0.00088%, 1/113770 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.142
- BayesDel
- -0.253
How the predictions were used
PP3 N/APer 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- VCEP restricts PP3 to synonymous/intronic variants only
Sources
BP4 VCEPBP4 is not applicable per SCID VCEP specifications for JAK3. Details ▾Hide ▴
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous/deep intronic variants per SCID VCEP
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.25). REVEL score = 0.142. BayesDel score = -0.252601.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25193870 ↗JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model.Degryse et al. characterized 12 JAK3 mutations identified in T-ALL, including the pseudokinase domain mutant M511I (p.Met511Ile). The paper demonstrates that M511I transforms Ba/F3 cells to cytokine-independent growth, signals through JAK1/STAT5/ERK, and causes T-ALL in a mouse bone marrow transplant model. NM_000215.3:c.1531A>G (p.Met511Val) was not studied or mentioned in this paper.Does not name this variant
Quoted passage
These mutations included FERM/SH2 domain mutations (R272H, R403H), pseudokinase domain mutations (M511I, A572T, A573V, R657W, R657Q, V674A, V678M), and kinase domain mutations (L857Q, R925S, E1106G)
Results paragraph 1 — 12 JAK3 mutants listed; M511I is among pseudokinase domain mutations studied
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
10 / 1,614,018 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.250
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1567011281
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000215.3%3Ac.1531A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-17949110-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-17838301-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-17838301-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000215.3%3Ac.1531…
- OncoKB ↗www.oncokb.org/gene/JAK3/M511V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=JAK3+c.1531A%3EG
- 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= 6.19572e-06; MAF= 0.00062%, 10/1614018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-06; MAF= 0.00085%, 10/1180036 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97621e-06; MAF= 0.00040%, 1/251496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78966e-06; MAF= 0.00088%, 1/113770 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.25). REVEL score = 0.142. BayesDel score = -0.252601.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. JAK3, a non-receptor tyrosine kinase, is recurrently altered by mutation in hematologic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.