SH2B3 c.631A>G, p.Met211Val
NM_005475.2:c.631A>G
Variant of Uncertain Significance (VUS)
This variant is classified as VUS due to absence of strong pathogenic or benign evidence. It is extremely rare (PM2) but computationally predicted benign (BP4), with no functional, segregation, or phenotype data to support a definitive classification.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
SH2B3
Transcript
NM_005475.3
MANE Select
Total Exons
8
Strand
Forward (+)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_005475.1 | Alternative | 8 exons | Forward |
| NM_005475.2 | RefSeq Select | 8 exons | Forward |
Variant Details
HGVS Notation
NM_005475.2:c.631A>G
Protein Change
M211V
Location
Exon 2
(Exon 2 of 8)
5'Exon Structure (8 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 211 in gene SH2B3
Variant interpretation based on transcript NM_005475.3
Genome Browser
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HGVS InputNM_005475:c.631A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00186%
Rare
Highest in Population
European (non-Finnish)
0.00464%
Rare
Global: 0.00186%
European (non-Finnish): 0.00464%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 107566Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00186%, 2/107566 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00464%, 2/43126 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 211 in gene SH2B3
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.032
0.032
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Benign
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 2.60sift: Tpolyphen_prediction: benignmutationassessor: Lprovean: Nmetasvm: Tmetalr: Tdeogen2: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease". The evidence for this variant shows: M211V is a missense change, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null type.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant regardless of nucleotide change". The evidence for this variant shows: there is no reported pathogenic variant with the same M211V amino acid change. Therefore, this criterion is not applied at Not Applied strength because no matching pathogenic amino acid change is known.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo data or parental testing is available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assayed.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case–control or affected‐individual data are available. Therefore, this criterion is not applied at Not Applied strength because there is no prevalence data in affected cohorts.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no information on a mutational hotspot or characterized functional domain at residue 211. Therefore, this criterion is not applied at Not Applied strength because domain/hotspot annotation is lacking.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: extremely rare in population databases (gnomAD MAF=0.00186%, no homozygotes). Therefore, this criterion is applied at Moderate strength because the variant meets the rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on zygosity or phase with another variant. Therefore, this criterion is not applied at Not Applied strength because trans phasing information is not available.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a missense substitution with no change in length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense changes reported at residue M211. Therefore, this criterion is not applied at Not Applied strength because no precedent pathogenic variant exists at this site.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no family testing or de novo assumption data. Therefore, this criterion is not applied at Not Applied strength because de novo status is not established.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation or family data. Therefore, this criterion is not applied at Not Applied strength because segregation evidence is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: gene‐level missense constraint or disease mechanism data are not available. Therefore, this criterion is not applied at Not Applied strength because gene-level missense tolerance is unknown.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational tools (REVEL=0.03, CADD, SIFT, PolyPhen-2, etc.) predict benign impact and no splicing effect. Therefore, this criterion is not applied at Not Applied strength because predictions do not support deleteriousness.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no clinical phenotype or family history information is provided. Therefore, this criterion is not applied at Not Applied strength because phenotype data are missing.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar classifies it as VUS in two laboratories. Therefore, this criterion is not applied at Not Applied strength because no reputable pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (>5%)". The evidence for this variant shows: MAF=0.00186%, far below the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not high enough.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: frequency is extremely low (0.00186%), below expected thresholds. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no information on healthy adult carriers with confirmed penetrance. Therefore, this criterion is not applied at Not Applied strength because healthy carrier data are unavailable.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional assays have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional studies are absent.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: the disease mechanism for SH2B3 is not established as exclusively LoF. Therefore, this criterion is not applied at Not Applied strength because mechanism data are insufficient.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: no data on co-occurrence or phasing with other variants. Therefore, this criterion is not applied at Not Applied strength because variant phasing is unknown.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a single‐nucleotide missense substitution, not an in‐frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: REVEL score 0.03, CADD, SIFT, PolyPhen-2, MutationAssessor, PROVEAN, MetaSVM, MetaLR, DEOGEN2 all predict benign, and SpliceAI shows no splice alteration. Therefore, this criterion is applied at Supporting strength because computational predictions consistently indicate benign impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no reports of the variant co-occurring with an alternative molecular cause. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no reputable benign assertions (ClinVar reports VUS). Therefore, this criterion is not applied at Not Applied strength because no benign assertion exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense substitution, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.