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This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
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 applied · 16 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
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 v2.1: 2/251006 alleles (AF=7.97e-06)0 homozygotes
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
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 max delta score: 0.03 — no predicted donor gaindonor lossacceptor gain
spliceai ↗
Assessed · not applied
Pathogenic
PS2 No de novo data available for this variant in any source.
PS3 No well-established functional study data available.
PS4 No case-control or cohort data available.
PM6 No de novo data available for this variant; PM6 cannot be assessed without confirmed maternity/paternity and de novo observation.
PP1 No cosegregation data available for this variant.
PP3 Multiple lines of computational evidence do not support a deleterious effect.
PP4 No patient phenotype or family history data available for this variant.
PP5 Variant is absent from ClinVar; no reputable source has independently classified this variant.
Benign
BA1 gnomAD allele frequency far below BA1 threshold of >1%.
BS1 gnomAD allele frequency far below BS1 threshold of >0.3%.
BS2 No homozygotes observed in gnomAD (v2.1: 0 homozygotes among 251,006 alleles; v4.1: 0 homozygotes among 1,612,940 alleles).
BS3 No well-established functional study data available demonstrating no deleterious effect for this variant.
BS4 No nonsegregation data available for this variant.
BP2 No data on observation in trans with a pathogenic variant in SH2B3.
BP5 No data on observation of this variant in a case with an alternate molecular basis for disease.
BP6 Variant is absent from ClinVar; no reputable source has reported this variant as benign.
N/A · 10 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
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