About SH2B3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SH2B3 c.419G>C, p.(Arg140Pro)
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
NM_005475.2:c.419G>C is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (3/1,472,034 alleles; AF=0.00020%), well below the 0.1% threshold for PM2. No homozygotes observed. The variant is absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.165 (below the 0.5 pathogenic threshold, predicting benign). BayesDel score is -0.347 (negative score predicts benign). SpliceAI delta score is 0.00 (no predicted splice impact). These concordant benign predictions from independent in silico tools support BP4 at supporting benign strength.
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
3 / 1,472,034 alleles
gnomAD v4.1: 3 / 1,472,034 alleles. Recorded AF 2.038e-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. 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
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 Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 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.419G>C (p.Arg140Pro) is a missense variant in SH2B3 exon 2 that is absent from ClinVar and present at extremely low frequency in gnomAD v4.1 (3/1,472,034 alleles; AF=0.00020%).
PM2 (supporting) is met: the variant is at extremely low population frequency, well below the 0.1% threshold.
BP4 (supporting benign) is met: concordant in silico predictions from REVEL (0.165) and BayesDel (-0.347) indicate a benign effect, and SpliceAI predicts no splice alteration (max delta 0.00).
PVS1 is not applicable as this is a missense variant that does not fall into any null-variant category per ClinGen SVI PVS1 recommendations.
No pathogenic or benign criteria beyond PM2 and BP4 are met. No variant-specific functional data, clinical observations, de novo events, segregation data, or literature reports exist for this variant.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced with a slight lean toward uncertain significance given the absence of any functional or clinical data.
No criteria match.
Met · 2
PM2 SupportingNM_005475.2:c.419G>C is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (3/1,472,034 alleles; AF=0.00020%), well below the 0.1% threshold for PM2. No homozygotes observed. The variant is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=2.038e-06 (0.00020%)
- 3/1
- 472
- 034 alleles
- 0 homozygotes
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.165 (below the 0.5 pathogenic threshold, predicting benign). BayesDel score is -0.347 (negative score predicts benign). SpliceAI delta score is 0.00 (no predicted splice impact). These concordant benign predictions from independent in silico tools support BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.165 (benign)
- BayesDel: -0.347 (benign)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No alternate nucleotide change at codon 140 producing the same Arg140Pro missense change has been reported as pathogenic. ClinVar contains no entries for this residue in SH2B3. PS1 requires a different nucleotide substitution leading to the same amino acid alteration with established pathogenicity, which is absent here. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at codon 140 in SH2B3
- PM5 candidate search found zero same-residue comparators
Still missing
- No alternative nucleotide changes at codon 140 identified in any database
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation has been reported for NM_005475.2:c.419G>C. PS2 requires a de novo variant with confirmed maternity and paternity in a patient with the disease and no family history. No such data exists for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available across ClinVar
- literature
- or cohort databases
Still missing
- No familial or de novo testing data for this variant
PS3 No variant-specific functional studies have been reported for NM_005475.2:c.419G>C (p.Arg140Pro). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publications identified through literature triage mention this variant. Absent from COSMIC and hotspot databases. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific functional evidence
- COSMIC: not reported in somatic cancers
- Cancer Hotspots: not in a statistically significant hotspot
- No publications identified for this variant
Still missing
- No experimental functional characterization of p.Arg140Pro
Sources
PS4 No case-control or cohort prevalence data exist for this variant. The variant is absent from ClinVar and has not been reported in any affected individual. PS4 requires a statistically significant enrichment in affected individuals compared with controls, which cannot be assessed here. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — zero affected individuals reported
- gnomAD v4.1: 3/1
- 472
- 034 alleles (AF=0.00020%) — extremely rare
- no enrichment data
Still missing
- No case-control studies or affected-individual reports for this variant
Sources
PM1 Residue 140 does not lie within a statistically significant mutational hotspot per cancerhotspots.org. While SH2B3 contains known functional domains (PH domain approximately residues 20–120; SH2 domain approximately residues 400–475), position 140 falls between these domains with no evidence that this specific region constitutes a critical, well-established functional domain where missense variants are known to be pathogenic. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue 140 not in a statistically significant hotspot
- No domain-level characterization identifying position 140 as critical for SH2B3 function
Still missing
- No systematic functional characterization of the region surrounding residue 140
Sources
PM5 No pathogenic missense variant at codon 140 has been identified in ClinVar or other databases. The PM5 candidate search found zero same-residue comparator variants. PM5 requires a different amino acid change at the same residue to have been previously established as pathogenic. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- ClinVar: no entries at codon 140 in SH2B3
Still missing
- No pathogenic comparator variants at codon 140
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation has been reported for this variant. PM6 requires a de novo variant without confirmed paternity and maternity. No such data is available. Details ▾Hide ▴
Evidence considered
- No de novo data available
Still missing
- No de novo testing data
PP1 No cosegregation data is available for this variant. PP1 requires cosegregation with disease in multiple affected family members. No familial studies exist for NM_005475.2:c.419G>C. Details ▾Hide ▴
Evidence considered
- No family studies or cosegregation data
Still missing
- No familial segregation analysis
PP2 Insufficient data to evaluate whether SH2B3 has a low rate of benign missense variation and whether missense variants are a common disease mechanism. No gene-level constraint metrics (Z-score, missense depletion) are available for SH2B3 in the evidence summary, and the HCI prior is not available for this gene. Details ▾Hide ▴
Evidence considered
- HCI prior not available for SH2B3
- No gene-level missense constraint metrics available
Still missing
- Gene-level missense constraint data (e.g.
- gnomAD Z-score) not assessed
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.165 (below the 0.5 pathogenic threshold). BayesDel score is -0.347 (negative score predicts benign). SpliceAI predicts no splice impact (max delta = 0.00). These predictions do not support a damaging effect; PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.165 (benign-predicting)
- BayesDel: -0.347 (benign-predicting)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP4 No patient phenotype data is available for this variant. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. No clinical context exists. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available
Still missing
- No patient phenotype or clinical context
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar. OncoKB classifies it as 'Unknown Oncogenic Effect.' No expert panel or clinical laboratory has classified this variant. Details ▾Hide ▴
BA1 The overall allele frequency in gnomAD v4.1 is 0.00020% (AF=2.038e-06), well below the BA1 threshold of >1%. This variant is not a common polymorphism. Details ▾Hide ▴
BS1 The allele frequency in gnomAD v4.1 is 0.00020%, below the BS1 threshold of >0.3%. Additionally, the variant is absent from gnomAD v2.1, further supporting that it is not observed at a frequency expected for a benign variant. Details ▾Hide ▴
BS2 No homozygous individuals are observed in gnomAD v4.1 (0/1,472,034 alleles). BS2 requires observation in a healthy adult homozygous state for a fully penetrant dominant disorder. The absence of homozygotes precludes application of this criterion. Details ▾Hide ▴
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect on the SH2B3 gene product for this variant. No functional data of any kind exists for p.Arg140Pro. Details ▾Hide ▴
Evidence considered
- No functional studies available for this variant
Still missing
- No experimental functional characterization
BS4 No segregation data is available for this variant. BS4 requires lack of segregation with disease in affected family members. No family studies exist. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data
Still missing
- No familial segregation analysis
BP1 While this is a missense variant, loss of function is an established disease mechanism for SH2B3 based on germline literature supporting biallelic SH2B3 alterations in hematopoietic disorders. BP1 requires that the gene primarily causes disease through truncating variants only, which is not the case for SH2B3 where missense and LoF variants have both been implicated. Details ▾Hide ▴
Evidence considered
- SH2B3 LoF is a supported germline disease mechanism per targeted literature review
- BP1 does not apply when missense variants are also a recognized disease mechanism
Sources
pvs1_gene_context
BP2 No data regarding observation in trans with a known pathogenic variant is available. BP2 requires observation in trans with a pathogenic variant in a gene for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase data available
Still missing
- No cis/trans phase information
BP5 No alternate molecular basis for disease has been identified in an individual harboring this variant. BP5 requires a variant found in a case with an alternate molecular basis for disease, which is not available here. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified
Still missing
- No clinical case with alternate molecular diagnosis
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar, and no clinical or expert panel has classified it. OncoKB reports 'Unknown Oncogenic Effect,' which is not equivalent to a benign classification. Details ▾Hide ▴
PS5 No established functional studies demonstrate a damaging effect on the SH2B3 gene or gene product for this variant. No experimental data exists for p.Arg140Pro. PS5 (extended framework) requires well-established functional data showing a deleterious effect, which is absent. Details ▾Hide ▴
Evidence considered
- No functional data available for this variant
Still missing
- No functional characterization of p.Arg140Pro
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_005475.2:c.419G>C is a missense substitution (p.Arg140Pro) that does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), the generic PVS1 framework is not triggered for this variant class. Details ▾Hide ▴
Evidence considered
- Missense variant — not a predicted null variant
- PVS1 decision tree assigns to bucket 'other'
- generic framework not applicable
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or creation of a new splice site. NM_005475.2:c.419G>C is a missense variant (p.Arg140Pro), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant — BP7 only applicable to synonymous variants
Identifiers
- Gene
- SH2B3
- Transcript
- NM_005475.2
- Coding (HGVS c.)
- NM_005475.2:c.419G>C
- Protein (HGVS p.)
- NP_005466.1:p.(Arg140Pro)
- GRCh38
- chr12:111418564 G>C
- GRCh37
- chr12:111856368 G>C
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
3 / 1,472,034 alleles
AF 2.04e-06 · 0 homozygotes · FAF 7.2e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2e-06 · 3 / 1,472,034 alleles · 0 hom · FAF 7.2e-07
| European (non-Finnish)3 / 1,117,320 | 2.7e-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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.038e-06; MAF= 0.00020%, 3/1472034 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.685e-06; MAF= 0.00027%, 3/1117320 alleles, homozygotes = 0); grpmax FAF= 7.2e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.165
- BayesDel
- -0.347
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.165 (below the 0.5 pathogenic threshold, predicting benign). BayesDel score is -0.347 (negative score predicts benign). SpliceAI delta score is 0.00 (no predicted splice impact). These concordant benign predictions from independent in silico tools support BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.165 (benign)
- BayesDel: -0.347 (benign)
- SpliceAI: max delta 0.00 (no splice effect)
Sources
PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.165 (below the 0.5 pathogenic threshold). BayesDel score is -0.347 (negative score predicts benign). SpliceAI predicts no splice impact (max delta = 0.00). These predictions do not support a damaging effect; PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.165 (benign-predicting)
- BayesDel: -0.347 (benign-predicting)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or creation of a new splice site. NM_005475.2:c.419G>C is a missense variant (p.Arg140Pro), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant — BP7 only applicable to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.165. BayesDel score = -0.347111.
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
3 / 1,472,034 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_005475.2%3Ac.419G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-111856368-G-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-111418564-G-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-111418564-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005475.2%3Ac.419G…
- OncoKB ↗www.oncokb.org/gene/SH2B3/R140P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SH2B3+c.419G%3EC
- 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= 2.038e-06; MAF= 0.00020%, 3/1472034 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.685e-06; MAF= 0.00027%, 3/1117320 alleles, homozygotes = 0); grpmax FAF= 7.2e-07.
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 = 0.165. BayesDel score = -0.347111.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.