About SH2B3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SH2B3 c.127C>T, p.(Arg43Cys)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
PM2 (supporting) is met: NM_005475.2:c.127C>T is present in gnomAD at a total allele frequency of 0.045% (695/1,540,252 alleles in v4.1; 41/172,716 in v2.1), which falls below the 0.1% threshold for PM2. Homozygotes are absent. However, the presence of 695 alleles across gnomAD v4.1 indicates this is not an ultra-rare variant, limiting strength to supporting.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
BP4 (supporting benign) is met: multiple lines of computational evidence suggest NM_005475.2:c.127C>T (p.Arg43Cys) has no deleterious impact. REVEL score is 0.254 (below pathogenic threshold), BayesDel score is -0.346 (predicts benign), and SpliceAI predicts no splicing alteration (max delta 0.00). All three independent in silico tools concur in predicting a neutral effect.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
695 / 1,540,252 alleles
gnomAD v4.1: 695 / 1,540,252 alleles. Recorded AF 0.000451225. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000237384; MAF= 0.02374%, 41/172716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000512522; MAF= 0.05125%, 37/72192 alleles, homozygotes = 0); grpmax FAF= 0.00040972.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 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
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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. SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias an
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV99049927, n = 3 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 · 3 not met · 7 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_005475.2:c.127C>T (p.Arg43Cys) is a missense variant in SH2B3, a gene for which loss of function is a supported germline disease mechanism in myeloid and myeloproliferative disorders.
This variant is present in gnomAD v4.1 at a total allele frequency of 0.045% (695/1,540,252 alleles) and in v2.1 at 0.024% (41/172,716 alleles), with no homozygotes observed. The highest subpopulation frequency is 0.059% in the European (non-Finnish) population. These frequencies fall below the 0.1% threshold for PM2 at supporting level.
Multiple in silico tools predict a benign effect: REVEL score 0.254 (below pathogenic threshold), BayesDel score -0.346 (predicts benign), and SpliceAI max delta 0.00 (no splicing impact). This meets BP4 at supporting benign level.
This variant is classified as Uncertain significance in ClinVar (1 submitter, GeneDx). OncoKB reports an Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications specifically mentioning NM_005475.2:c.127C>T were identified.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced toward neither pathogenic nor benign. Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant remains a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingPM2 (supporting) is met: NM_005475.2:c.127C>T is present in gnomAD at a total allele frequency of 0.045% (695/1,540,252 alleles in v4.1; 41/172,716 in v2.1), which falls below the 0.1% threshold for PM2. Homozygotes are absent. However, the presence of 695 alleles across gnomAD v4.1 indicates this is not an ultra-rare variant, limiting strength to supporting. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF 0.045% (695/1
- 540
- 252 alleles
- 0 homozygotes)
- grpmax FAF 0.055%
- gnomAD v2.1: AF 0.024% (41/172
- 716 alleles
- grpmax FAF 0.041%
- gnomAD-Canada v1.0: AF 0.016% (3/18
- 420 alleles
- Highest subpopulation frequency: European (non-Finnish) at 0.059% in v4.1
Sources
BP4 SupportingBP4 (supporting benign) is met: multiple lines of computational evidence suggest NM_005475.2:c.127C>T (p.Arg43Cys) has no deleterious impact. REVEL score is 0.254 (below pathogenic threshold), BayesDel score is -0.346 (predicts benign), and SpliceAI predicts no splicing alteration (max delta 0.00). All three independent in silico tools concur in predicting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.254 (below 0.5 pathogenic threshold
- predicts benign)
- BayesDel score: -0.346 (negative score
- SpliceAI max delta: 0.00 (no splicing impact predicted)
Sources
Not met · 3 · evaluated, threshold not reached
PP3 PP3 is not met: multiple in silico tools predict a benign effect for NM_005475.2:c.127C>T (p.Arg43Cys). REVEL score is 0.254 (well below the 0.5 pathogenic threshold), BayesDel score is -0.346 (negative score favors benign), and SpliceAI predicts no splicing impact (max delta 0.00). No computational tool supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.254 (below 0.5 pathogenic threshold)
- BayesDel score: -0.346 (negative
- predicts benign)
- SpliceAI max delta: 0.00 (no splicing impact predicted)
Sources
BA1 BA1 is not met: the highest observed population allele frequency is 0.059% (European non-Finnish in gnomAD v4.1), which is far below the 1% BA1 threshold. This variant is not sufficiently common to be considered a benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.059% (NFE)
- gnomAD v2.1 max subpopulation AF: 0.051% (NFE)
- All frequencies well below BA1 threshold of 1%
Sources
BS1 BS1 is not met: the highest observed population allele frequency is 0.059% (European non-Finnish in gnomAD v4.1), which is below the 0.3% BS1 threshold. The variant is not sufficiently frequent in population databases to support a benign interpretation via allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.059% (NFE)
- gnomAD v2.1 max subpopulation AF: 0.051% (NFE)
- All frequencies below BS1 threshold of 0.3%
Sources
Not assessed · 7 · no assessment recorded
PS2 PS2 cannot be assessed: no de novo data are available. No publications, family studies, or trio sequencing data were identified for NM_005475.2:c.127C>T. Details ▾Hide ▴
Still missing
- No de novo testing data available
- parental studies would be required to assess PS2
PS3 PS3 cannot be assessed: no variant-specific functional studies were identified for NM_005475.2:c.127C>T (p.Arg43Cys). OncoKB reports 'Unknown Oncogenic Effect' with no curated functional evidence. No publications with functional assays for this specific variant were found. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence curated
Still missing
- No functional studies available
- in vitro assays (e.g.
- reporter assays
- cytokine signaling readouts) would be needed to assess PS3
Sources
PM6 PM6 cannot be assessed: no de novo data are available for NM_005475.2:c.127C>T. No publications report de novo occurrence of this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 PP1 cannot be assessed: no segregation data are available for NM_005475.2:c.127C>T. No family studies or co-segregation analyses were identified. Details ▾Hide ▴
Still missing
- No family segregation data available
BS2 BS2 cannot be assessed: although NM_005475.2:c.127C>T is observed in 695 heterozygous individuals in gnomAD v4.1, no phenotype data are available for these carriers. Without confirmed healthy adult status, BS2 cannot be applied. Details ▾Hide ▴
Evidence considered
- 695 heterozygous carriers in gnomAD v4.1
- but phenotype unknown
Still missing
- Phenotype data on heterozygous carriers would be needed to assess BS2
Sources
BS3 BS3 cannot be assessed: no variant-specific functional studies demonstrating a neutral or benign effect for NM_005475.2:c.127C>T are available. While in silico tools predict a benign impact (see BP4), these are computational predictions, not experimental functional evidence meeting BS3 standards. Details ▾Hide ▴
Still missing
- No experimental functional studies demonstrating no damaging effect
BS4 BS4 cannot be assessed: no segregation data demonstrating lack of co-segregation with disease are available for NM_005475.2:c.127C>T. Details ▾Hide ▴
Still missing
- No family segregation data available
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_005475.2:c.127C>T is a missense variant (p.Arg43Cys), which does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application under ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant bucket is 'other' (missense substitution)
- apply_generic_pvs1_framework is false per pvs1_variant_assessment.json
Sources
PS1 N/APS1 is not applicable: no prior pathogenic variant at residue Arg43 with a different nucleotide change has been identified. No alternative pathogenic missense change at the same codon is recorded in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains only NM_005475.2:c.127C>T (p.Arg43Cys) at this residue
- classified as VUS
- no known pathogenic comparator at Arg43
Sources
PS4 N/APS4 is not applicable: no case-control or statistical enrichment data are available for NM_005475.2:c.127C>T. The variant has no published association studies comparing affected vs. unaffected populations. Details ▾Hide ▴
No further detail was recorded.
PM1 N/APM1 is not applicable: residue Arg43 does not lie within an established mutational hotspot or well-characterized functional domain without benign variation. CancerHotspots reports no statistically significant hotspot at this residue. COSMIC records 3 somatic observations, which is below hotspot thresholds. Details ▾Hide ▴
Evidence considered
- CancerHotspots: no significant hotspot at SH2B3 R43
- COSMIC: COSV99049927
- 3 somatic observations
PM5 N/APM5 is not applicable: no pathogenic missense comparator variants at residue Arg43 were identified. The automated candidate search found zero same-residue candidates, and PM5 semantics could not be safely confirmed. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates
- no ClinVar pathogenic/likely pathogenic variants at Arg43
Sources
pm5_candidates
PP2 N/APP2 is not applicable: while SH2B3 loss of function is a supported germline disease mechanism, the specific requirement that missense variants are a common mechanism of disease with a low rate of benign missense variation could not be confirmed. SH2B3 missense constraint metrics (e.g., Z-score, observed/expected ratio) are not available in the evidence record. Details ▾Hide ▴
Evidence considered
- SH2B3 LoF mechanism supported per pvs1_gene_context
- but insufficient data on missense constraint to meet PP2 criteria
Still missing
- Missense constraint data (e.g.
- gnomAD missense Z-score or oe ratio) would be needed to evaluate PP2
PP4 N/APP4 is not applicable: no specific phenotype data or syndromic features are available to evaluate whether the patient's phenotype is highly specific for SH2B3-related disease. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 is not applicable: no reputable source has recently reported NM_005475.2:c.127C>T as pathogenic. The sole ClinVar submission (GeneDx) classifies it as Uncertain significance. Details ▾Hide ▴
BP1 N/ABP1 is not applicable: while SH2B3 loss of function is an established disease mechanism, the gene is not characterized as having disease caused primarily by truncating variants. Germline missense variants in SH2B3 have been reported in association with disease (e.g., myeloproliferative disorders), indicating that missense changes can also be pathogenic. Details ▾Hide ▴
Evidence considered
- Published literature describes both missense and truncating SH2B3 germline variants in disease contexts
- primarily truncating mechanism not established
Sources
pvs1_gene_context
BP2 N/ABP2 is not applicable: no evidence of NM_005475.2:c.127C>T observed in trans with a known pathogenic SH2B3 variant has been identified. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 is not applicable: no evidence of an alternate molecular basis for disease has been identified in a case carrying NM_005475.2:c.127C>T. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 is not applicable: no reputable source has reported NM_005475.2:c.127C>T as benign. ClinVar classifies this variant as Uncertain significance (1 submitter, GeneDx). Details ▾Hide ▴
BP7 N/ABP7 is not applicable: NM_005475.2:c.127C>T is a missense variant (p.Arg43Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact and non-conserved nucleotides. Details ▾Hide ▴
Evidence considered
- Variant type is missense (substitution)
- not synonymous
PS5 N/APS5 is not applicable: no reputable source has recently reported NM_005475.2:c.127C>T as pathogenic. The sole ClinVar submission classifies it as Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (GeneDx
- 1 submitter)
Sources
Identifiers
- Gene
- SH2B3
- Transcript
- NM_005475.2
- Coding (HGVS c.)
- NM_005475.2:c.127C>T
- Protein (HGVS p.)
- NP_005466.1:p.(Arg43Cys)
- GRCh38
- chr12:111418272 C>T
- GRCh37
- chr12:111856076 C>T
- ClinVar
- 3252447
- COSMIC
- COSV99049927
Gene diagram
Every interpreted variant in SH2B3, mapped onto the exon structure of NM_005475.2. Select a row to find it on the plot.
SH2B3NM_005475.2
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 SH2B3
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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
695 / 1,540,252 alleles
AF 0.000451 · 0 homozygotes · FAF 0.000554
gnomAD v2.1
41 / 172,716 alleles
AF 0.000237 · 0 homozygotes · FAF 0.00041
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00045 · 695 / 1,540,252 alleles · 0 hom · FAF 0.00055
| European (non-Finnish)680 / 1,150,452 | 0.00059 |
| Remaining individuals10 / 59,956 | 0.00017 |
| African/African American2 / 72,446 | 2.8e-05 |
| South Asian2 / 85,294 | 2.3e-05 |
| European (Finnish)1 / 44,982 | 2.2e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00024 · 41 / 172,716 alleles · 0 hom · FAF 0.00041
| European (non-Finnish)37 / 72,192 | 0.00051 |
| Remaining individuals2 / 5,264 | 0.00038 |
| South Asian1 / 23,744 | 4.2e-05 |
| Admixed American1 / 25,884 | 3.9e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000451225; MAF= 0.04512%, 695/1540252 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000591072; MAF= 0.05911%, 680/1150452 alleles, homozygotes = 0); grpmax FAF= 0.00055351.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000237384; MAF= 0.02374%, 41/172716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000512522; MAF= 0.05125%, 37/72192 alleles, homozygotes = 0); grpmax FAF= 0.00040972.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.254
- BayesDel
- -0.346
How the predictions were used
BP4 SupportingBP4 (supporting benign) is met: multiple lines of computational evidence suggest NM_005475.2:c.127C>T (p.Arg43Cys) has no deleterious impact. REVEL score is 0.254 (below pathogenic threshold), BayesDel score is -0.346 (predicts benign), and SpliceAI predicts no splicing alteration (max delta 0.00). All three independent in silico tools concur in predicting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.254 (below 0.5 pathogenic threshold
- predicts benign)
- BayesDel score: -0.346 (negative score
- SpliceAI max delta: 0.00 (no splicing impact predicted)
Sources
PP3 PP3 is not met: multiple in silico tools predict a benign effect for NM_005475.2:c.127C>T (p.Arg43Cys). REVEL score is 0.254 (well below the 0.5 pathogenic threshold), BayesDel score is -0.346 (negative score favors benign), and SpliceAI predicts no splicing impact (max delta 0.00). No computational tool supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.254 (below 0.5 pathogenic threshold)
- BayesDel score: -0.346 (negative
- predicts benign)
- SpliceAI max delta: 0.00 (no splicing impact predicted)
Sources
BP7 N/ABP7 is not applicable: NM_005475.2:c.127C>T is a missense variant (p.Arg43Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact and non-conserved nucleotides. Details ▾Hide ▴
Evidence considered
- Variant type is missense (substitution)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.254. BayesDel score = -0.345922.
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
695 / 1,540,252 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
1 Uncertain significance
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/variation/3252447/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-111856076-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-111418272-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-111418272-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005475.2%3Ac.127C…
- OncoKB ↗www.oncokb.org/gene/SH2B3/R43C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=130455920
- 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= 0.000451225; MAF= 0.04512%, 695/1540252 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000591072; MAF= 0.05911%, 680/1150452 alleles, homozygotes = 0); grpmax FAF= 0.00055351.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000237384; MAF= 0.02374%, 41/172716 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000512522; MAF= 0.05125%, 37/72192 alleles, homozygotes = 0); grpmax FAF= 0.00040972.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3252447)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.254. BayesDel score = -0.345922.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias an
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99049927, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.