SH2B3 c.1112G>C, p.Arg371Thr
NM_005475.2:c.1112G>C
Variant of Uncertain Significance (VUS)
Classified as Variant of Uncertain Significance because only PM2 (Moderate) and PP3 (Supporting) are met, with no additional pathogenic or benign evidence available.
ACMG/AMP Criteria Applied
PM2
PP3
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.1112G>C
Protein Change
R371T
Location
Exon 6
(Exon 6 of 8)
5'Exon Structure (8 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 371 in gene SH2B3
Variant interpretation based on transcript NM_005475.3
Genome Browser
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HGVS InputNM_005475:c.1112G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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 371 in gene SH2B3
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.941
0.941
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.95
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 (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (R371T), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet PVS1.
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 but different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant with the same amino acid change at residue 371 is reported. Therefore, this criterion is not applied at Not Applied strength because PS1 is not met.
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 status information is available. Therefore, this criterion is not applied at Not Applied strength because PS2 cannot be assessed.
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 for R371T in SH2B3. Therefore, this criterion is not applied at Not Applied strength because PS3 evidence is lacking.
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 segregation data demonstrating increased prevalence. Therefore, this criterion is not applied at Not Applied strength because PS4 is not met.
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 indicating R371 lies in a mutational hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because PM1 is not met.
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: not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
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 trans phase data or indication of recessive inheritance. Therefore, this criterion is not applied at Not Applied strength because PM3 is not met.
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, not an in‐frame indel or stop‐loss. Therefore, this criterion is not applied at Not Applied strength because PM4 is not met.
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 at residue R371 has been reported. Therefore, this criterion is not applied at Not Applied strength because PM5 is not met.
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 de novo or familial data. Therefore, this criterion is not applied at Not Applied strength because PM6 cannot be assessed.
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 data available. Therefore, this criterion is not applied at Not Applied strength because PP1 is not met.
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: insufficient gene‐specific missense intolerance data. Therefore, this criterion is not applied at Not Applied strength because PP2 cannot be confidently assessed.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: REVEL score 0.94, damaging predictions from PolyPhen, MetaSVM, MetaLR and PrimateAI. Therefore, this criterion is applied at Supporting strength because in silico tools consistently predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied at Not Applied strength because PP4 cannot be assessed.
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: no such reports in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength because PP5 is not met.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: allele frequency is 0% in gnomAD, not above threshold. Therefore, this criterion is not applied at Not Applied strength because BA1 is not met.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is 0%, below expected maximum. Therefore, this criterion is not applied at Not Applied strength because BS1 is not met.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no reports of observation in healthy adults. Therefore, this criterion is not applied at Not Applied strength because BS2 is not met.
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 studies performed. Therefore, this criterion is not applied at Not Applied strength because BS3 cannot be assessed.
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 segregation or non-segregation data. Therefore, this criterion is not applied at Not Applied strength because BS4 cannot be assessed.
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: SH2B3 disease mechanism not solely LoF. Therefore, this criterion is not applied at Not Applied strength because BP1 is not met.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on phase with other variants. Therefore, this criterion is not applied at Not Applied strength because BP2 cannot be assessed.
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: R371T is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because BP3 is not met.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational tools predict a deleterious effect. Therefore, this criterion is not applied at Not Applied strength because BP4 is contradicted by PP3 evidence.
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 such case data. Therefore, this criterion is not applied at Not Applied strength because BP5 cannot be assessed.
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 such reports exist. Therefore, this criterion is not applied at Not Applied strength because BP6 is not met.
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: R371T is a missense variant, not synonymous. Therefore, this criterion is not applied at Not Applied strength because BP7 is not met.