LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-28
Case ID: NM_004972.4_c.1849G_T_20261028_071535
Framework: ACMG/AMP 2015
Variant classification summary

NM_004972.4:c.1849G>T

JAK2  · NP_004963.1:p.(Val617Phe)  · NM_004972.4
GRCh37: chr9:5073770 G>T  ·  GRCh38: chr9:5073770 G>T
Gene: JAK2 Transcript: NM_004972.4
Final call
Pathogenic
PS3 strong PS4 strong PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
JAK2
Transcript
NM_004972.4
Protein
NP_004963.1:p.(Val617Phe)
gnomAD AF
0.0002932901928990148 (v4.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong functional studies show increased JAK2 kinase activity, constitutive signaling, and disease phenotypes.
2
Pathogenic: PS4 strong shows marked case enrichment, including a continuity-corrected OR of 228.27 with a 95% CI excluding 1.
3
Pathogenic: PP3 moderate is supported by REVEL 0.881 exceeding the 0.773 missense threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; PP3 moderate provides additional support.
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 Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no documented pathogenic alternate-nucleotide variant producing the same p.Val617Phe amino-acid change.
PS2 Not assessed Not assessed: no documented affected proband, family-history status, or confirmed maternity and paternity is available for this variant.
PS3 Met Met at strong strength: independent cellular, recombinant-protein, and murine assays show constitutive signaling, approximately threefold higher kinase activity (493±19 vs 150±9), and disease phenotypes.
PMID:21533163 PMID:19543316 PMID:15781101 PMID:15858187 PMID:15793561 PMID:29355841
PS4 Met Met: 40/45 cases versus 0/15 controls gives a continuity-corrected OR 228.27 (95% CI 11.90-4377.56), exceeding the >5.0 threshold with the CI excluding 1.0.
PMID:15793561 PMID:15781101 PMID:15858187
PM1 Not assessed Not assessed: p.Val617Phe is in the functional JH2 domain, but absence of benign variation in that domain is not established.
PMID:15793561 PMID:21533163 PMID:12351625
PM2 Not met Not met: gnomAD v4.1 AF is 0.00029329, exceeding the supplied PM2 cutoff of 0.0001.
gnomad_v2 gnomad_v4
PM3 N/A Not applicable: JAK2 p.Val617Phe is reported as an acquired somatic mutation, not a recessive inherited allele requiring trans-phase evidence.
PMID:15858187
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no validated pathogenic different missense change at JAK2 residue 617 is established in the supplied evidence.
PM6 Not assessed Not assessed: no case-specific parental testing or documented assumed de novo occurrence is available for this variant.
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or phenotype-consistent segregation data are documented for this variant.
PP2 Not assessed Not assessed: activating JAK2 missense disease mechanism is shown, but low benign-missense rate is not established.
PMID:15781101 PMID:15858187
PP3 Met Met at moderate strength: REVEL 0.881 meets the >=0.773 PP3 moderate threshold but remains below the >=0.932 strong threshold.
revel
PP4 Not assessed Not assessed: no patient-specific phenotype or family history is available to determine whether it is highly specific for a single-gene disease.
PP5 Not met Not met: ClinVar has zero exact-variant expert-panel submissions, so laboratory and aggregate pathogenic labels cannot trigger PP5.
clinvar
BA1 Not met Not met: maximum observed allele frequency is 0.000746066 in Ashkenazi Jewish individuals, far below the 0.05 BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: highest observed population AF is 0.000746066, below the generic 0.01 BS1 default and not evidence of excessive frequency.
gnomad_v2 gnomad_v4 PMID:15793561 PMID:15858187
BS2 Not assessed Not assessed: 17 gnomAD v4.1 homozygotes are unphenotyped and may reflect somatic clonal hematopoiesis, not healthy adults with constitutional homozygosity.
gnomad_v2 gnomad_v4 PMID:15793561 PMID:15858187
BS3 Not met Not met: no well-established assay shows absence of damaging effect; tested systems consistently show constitutive signaling and increased kinase activity.
PMID:21533163 PMID:19543316 PMID:15781101 PMID:15858187 PMID:15793561 PMID:29355841
BS4 Not assessed Not assessed: no affected relatives with documented negative testing or family non-segregation analysis are available.
BP1 Not met Not met: JAK2 disease evidence centers on recurrent activating missense variants, not primarily truncating variants.
PMID:15781101 PMID:15858187 PMID:21533163
BP2 Not met Not met: the reported homozygosity reflects the same somatic JAK2 variant, with no distinct pathogenic variant documented in trans or cis.
PMID:15858187
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.881 exceeds the <=0.29 BP4 supporting threshold, and the missense rule excludes SpliceAI as a substitute.
revel
BP5 Not assessed Not assessed: no patient-level evidence shows this exact variant in a case with an alternate molecular basis for disease.
BP6 Not met Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is present to trigger BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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