Variant classification summary

NM_005475.2:c.*2C>T

SH2B3 · NP_005466.1:p.? · NM_005475.2

GRCh37: chr12:111886108 C>T · GRCh38: chr12:111448304 C>T

Gene: SH2B3 Transcript: NM_005475.2

Final call

VUS

PM2 supporting

Variant details

Gene

SH2B3

Transcript

NM_005475.2

Protein

NP_005466.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The SH2B3 c.*2C>T (NP_005466.1:p.?) variant has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the usual PM2 threshold of 0.001 (0.1%).

3

Although SH2B3 loss of function is an established disease mechanism, this variant is a 3'UTR substitution rather than a nonsense, frameshift, or canonical splice variant, so generic PVS1 criteria do not apply.

4

In silico splice prediction does not support a splice-altering effect, with a SpliceAI maximum delta score of 0.04.

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	Although SH2B3 loss of function is an established germline disease mechanism, this variant is a 3'UTR substitution and does not fall into the generic PVS1 null-variant categories such as nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this 3'UTR variant does not create the same amino acid change as a previously established pathogenic variant.
PS2	Not assessed	No confirmed de novo data with verified maternity and paternity were identified for this variant, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.
PS4	Not met	This variant has not been reported in ClinVar, and no case-control or enrichment data showing increased prevalence in affected individuals were identified, so PS4 is not met.	clinvar
PM1	Not assessed	No established mutational hotspot or well-characterized critical functional region supporting PM1 at this 3'UTR position was identified.
PM2	Met	This variant is absent from population databases reviewed. It was not observed in gnomAD v2.1 or gnomAD v4.1, which is below the usual PM2 rarity threshold of less than 0.001 (0.1%), supporting PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder, so PM3 was not assessed.
PM4	N/A	PM4 is not applicable because this variant does not change protein length and is located in the 3'UTR.
PM5	N/A	PM5 is not applicable because this variant is in the 3'UTR and does not alter an amino acid residue where a different pathogenic missense change has been established.
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a damaging splice effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, which is below commonly used concern thresholds, so PP3 is not met.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified showing a clinical presentation highly specific for a disorder caused by this variant, so PP4 was not assessed.
PP5	Not assessed	No pathogenic assertion from a reputable source was identified for this variant, so PP5 was not assessed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is below the BA1 threshold of 0.01 (1%) and BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is below the BS1 threshold of 0.003 (0.3%) and BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No direct evidence was identified showing this variant in healthy adult individuals in a context appropriate for BS2, so BS2 was not assessed.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed.
BS4	Not assessed	No family studies showing lack of cosegregation with disease were identified for this variant, so BS4 was not assessed.
BP1	N/A	BP1 is not applicable because this is not a missense variant.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a relevant setting, so BP2 was not assessed.
BP3	N/A	BP3 is not applicable because this is not an in-frame insertion or deletion in a repetitive region.
BP4	Not met	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, but this isolated splice prediction does not fully establish a benign effect for a 3'UTR regulatory variant. Therefore BP4 is not met.	spliceai
BP5	Not assessed	No alternate molecular explanation for the reported phenotype was identified from the available evidence, so BP5 was not assessed.
BP6	Not assessed	No benign assertion from a reputable source was identified for this variant, so BP6 was not assessed.	clinvar
BP7	N/A	BP7 is not applicable because this variant is not a synonymous or intronic change outside splice regions; it is a 3'UTR substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.