Variant classification summary

NM_005475.2:c.127C>T

SH2B3 · NP_005466.1:p.(Arg43Cys) · NM_005475.2

GRCh37: chr12:111856076 C>T · GRCh38: chr12:111418272 C>T

Gene: SH2B3 Transcript: NM_005475.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

SH2B3

Transcript

NM_005475.2

Protein

NP_005466.1:p.(Arg43Cys)

gnomAD AF

0.0004512248645026918 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 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).	pvs1_generic_framework
PS1	N/A	PS1 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.	clinvar
PS2	Not assessed	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.
PS3	Not assessed	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.	oncokb
PS4	N/A	PS4 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.
PS5	N/A	PS5 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.	clinvar
PM1	N/A	PM1 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.
PM2	Met	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.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not assessed	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.
PP2	N/A	PP2 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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	N/A	PP4 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.
PP5	N/A	PP5 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.	clinvar
BA1	Not met	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.	gnomad_v4 gnomad_v2
BS1	Not met	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.	gnomad_v4 gnomad_v2
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	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.
BS4	Not assessed	BS4 cannot be assessed: no segregation data demonstrating lack of co-segregation with disease are available for NM_005475.2:c.127C>T.
BP1	N/A	BP1 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.	pvs1_gene_context
BP2	N/A	BP2 is not applicable: no evidence of NM_005475.2:c.127C>T observed in trans with a known pathogenic SH2B3 variant has been identified.
BP4	Met	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.	revel bayesdel spliceai
BP5	N/A	BP5 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.
BP6	N/A	BP6 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).	clinvar
BP7	N/A	BP7 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.

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