NM_005475.2:c.419G>C

SH2B3 · NP_005466.1:p.(Arg140Pro) · NM_005475.2

GRCh37: chr12:111856368 G>C · GRCh38: chr12:111418564 G>C

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.(Arg140Pro)

gnomAD AF

2.0379964049743415e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar pm5_candidates
PS2	Not met	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.
PS3	Not met	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.	oncokb
PS4	Not met	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.	clinvar gnomad_v4
PS5	Not met	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.
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not met	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.
PP1	Not met	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.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar oncokb
BA1	Not met	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.	gnomad_v4 gnomad_v2
BS1	Not met	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.	gnomad_v4 gnomad_v2
BS2	Not met	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.	gnomad_v4
BS3	Not met	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.
BS4	Not met	No segregation data is available for this variant. BS4 requires lack of segregation with disease in affected family members. No family studies exist.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar oncokb
BP7	N/A	BP7 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.

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