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SH2B3
Final classification
VUS
SH2B3 c.835-15C>T · p.?
SH2B3

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).

Gene
SH2B3
Transcript
NM_005475.2
HGVS · transcript:coding
NM_005475.2:c.835-15C>T
Consequence
N/A
GRCh38
chr12:111446927 C>T
GRCh37
chr12:111884731 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2 BP4 VUS
SH2B3 c.835-15C>T

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).1 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.2 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).3

PM2 + BP4 → VUS
1 spliceai ↗
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 clinvar ↗
Gene diagram · NM_005475.2 · variants mapped to exon structure
SH2B3 NM_005475.2
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 1.79796e-05; MAF= 0.00180%, 29/1612940 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.45988e-05; MAF= 0.00246%, 29/1178920 alleles, homozygotes = 0); grpmax FAF= 1.726e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 7.96794e-06; MAF= 0.00080%, 2/251006 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76336e-05; MAF= 0.00176%, 2/113420 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0018% · 29 / 1,612,940
      0 hom · FAF 0.0017%
      European (non-Finnish)
      29 / 1,178,920
      0.0025%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.0008% · 2 / 251,006
      0 hom · FAF 0.00029%
      European (non-Finnish)
      2 / 113,420
      0.0018%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      7Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC