NM_005475.2:c.835-15C>T

SH2B3 · NP_005466.1:p.? · NM_005475.2

GRCh37: chr12:111884731 C>T · GRCh38: chr12:111446927 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.?

gnomAD AF

1.797959006534651e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005475.2:c.835-15C>T is an intronic SH2B3 variant located 15 bases upstream of exon 3. It is not a canonical splice site variant and SpliceAI predicts no splicing impact (max delta 0.03).

The variant is extremely rare in population databases: gnomAD v2.1 AF=7.97e-06 (2/251,006 alleles, 0 homozygotes) and gnomAD v4.1 AF=1.80e-05 (29/1,612,940 alleles, 0 homozygotes), meeting PM2 at supporting level.

No ClinVar entry, no publications mentioning this variant, and no functional data are available. The variant remains a Variant of Uncertain Significance (VUS) with one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4: SpliceAI predicts no splice impact).

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	Intronic variant (c.835-15C>T) does not fall into any ClinGen SVI PVS1 null-variant bucket: not a nonsense, frameshift, or canonical ±1,2 splice consensus variant. PVS1 is not applicable per PMC6185798.	pvs1_generic_framework
PS1	N/A	Intronic variant does not alter an amino acid; PS1 (same amino acid change as an established pathogenic variant) is not applicable.
PS2	Not assessed	No de novo data available for this variant in any source.
PS3	Not assessed	No well-established functional study data available. In silico tools (REVEL, BayesDel) do not score intronic positions. No functional assay publications identified for this variant.
PS4	Not assessed	No case-control or cohort data available. Variant is absent from ClinVar and no publications report this variant in affected individuals.
PS5	Not assessed	Variant is absent from ClinVar; no reputable source has independently classified this variant as pathogenic.	clinvar
PM1	N/A	Intronic variant does not reside in a known protein functional domain or mutational hot spot. PM1 is applicable to coding-region variants affecting critical residues or domains.
PM2	Met	Extremely low frequency in population databases, meeting PM2 threshold of <0.1%: gnomAD v2.1 AF=7.97e-06 (0.00080%, 2/251,006 alleles, 0 homozygotes), gnomAD v4.1 AF=1.80e-05 (0.00180%, 29/1,612,940 alleles, 0 homozygotes). Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Intronic variant does not produce an amino acid change; PM5 (same position, different pathogenic missense) is not applicable.
PM6	Not assessed	No de novo data available for this variant; PM6 cannot be assessed without confirmed maternity/paternity and de novo observation.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta=0.03, well below clinically meaningful thresholds for donor gain/loss and acceptor gain/loss). No other in silico predictors (REVEL, BayesDel) available for this intronic position.	spliceai
PP4	Not assessed	No patient phenotype or family history data available for this variant.
PP5	Not assessed	Variant is absent from ClinVar; no reputable source has independently classified this variant.	clinvar
BA1	Not met	gnomAD allele frequency far below BA1 threshold of >1%. Highest observed subpopulation AF: gnomAD v4.1 European (non-Finnish) AF=2.46e-05 (0.00246%).	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency far below BS1 threshold of >0.3%. Highest observed subpopulation AF: gnomAD v4.1 European (non-Finnish) AF=2.46e-05 (0.00246%).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes observed in gnomAD (v2.1: 0 homozygotes among 251,006 alleles; v4.1: 0 homozygotes among 1,612,940 alleles). No evidence of healthy adult homozygosity or compound heterozygosity with a pathogenic variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study data available demonstrating no deleterious effect for this variant.
BS4	Not assessed	No nonsegregation data available for this variant.
BP1	N/A	BP1 applies specifically to missense variants in genes where truncating variants are the predominant disease mechanism. This is an intronic substitution.
BP2	Not assessed	No data on observation in trans with a pathogenic variant in SH2B3.
BP4	Met	SpliceAI predicts no splicing alteration (max delta score = 0.03), well below clinically significant thresholds. For an intronic variant, splicing is the primary functional concern and SpliceAI is the most definitive computational predictor available. The very low delta score supports no impact on splicing.	spliceai
BP5	Not assessed	No data on observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not assessed	Variant is absent from ClinVar; no reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 applies specifically to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous coding variant.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a substitution.
PM3	N/A	PM3 (in trans with pathogenic variant in recessive disorder) not applicable — SH2B3-associated phenotypes show autosomal dominant or de novo inheritance patterns, and no trans-phase data available.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss); this is an intronic substitution.

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