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SH2B3c.835-15C>TUncertain significance
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Variant interpretation report

SH2B3 c.835-15C>T, p.?

NM_005475.2:c.835-15C>T NP_005466.1:p.? View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SH2B3

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
29 / 1,612,940 alleles

gnomAD v4.1: 29 / 1,612,940 alleles. Recorded AF 1.79796e-05. Recorded homozygote count 0.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 4 not met · 13 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 SupportingExtremely 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 2/251
  • 006 alleles (AF=7.97e-06)
  • 0 homozygotes
  • gnomAD v4.1: 29/1
  • 612
  • 940 alleles (AF=1.80e-05)
  • gnomAD-Canada: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.03 — no predicted donor gain
  • donor loss
  • acceptor gain
  • or acceptor loss above background.
Sources
spliceai ↗

Not met · 4 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.03 (no predicted splicing alteration).
Sources
spliceai ↗
BA1 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%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF=7.97e-06 (0.00080%)
  • gnomAD v4.1 total AF=1.80e-05 (0.00180%)
  • Highest subpopulation AF: gnomAD v4.1 NFE 2.46e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF=7.97e-06 (0.00080%)
  • gnomAD v4.1 total AF=1.80e-05 (0.00180%)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0 homozygotes
  • gnomAD v4.1: 0 homozygotes
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS2 No de novo data available for this variant in any source. Details ▾Hide ▴
Still missing
  • No parental testing or de novo reports identified.
PS3 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. Details ▾Hide ▴
Still missing
  • No functional studies (in vitro or in vivo) identified for this variant.
PS4 No case-control or cohort data available. Variant is absent from ClinVar and no publications report this variant in affected individuals. Details ▾Hide ▴
Still missing
  • No case-control or prevalence data available.
PM6 No de novo data available for this variant; PM6 cannot be assessed without confirmed maternity/paternity and de novo observation. Details ▾Hide ▴
Still missing
  • No de novo reports or trio data available.
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or segregation analysis reported.
PP4 No patient phenotype or family history data available for this variant. Details ▾Hide ▴
Still missing
  • No clinical context or proband phenotype data available.
PP5 Variant is absent from ClinVar; no reputable source has independently classified this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry found for this variant.
Sources
clinvar ↗
BS3 No well-established functional study data available demonstrating no deleterious effect for this variant. Details ▾Hide ▴
Still missing
  • No functional studies evaluating this specific variant identified.
BS4 No nonsegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or nonsegregation analysis reported.
BP2 No data on observation in trans with a pathogenic variant in SH2B3. Details ▾Hide ▴
Still missing
  • No phase information or co-occurrence data with known pathogenic SH2B3 variants.
BP5 No data on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No cases with an alternate molecular diagnosis identified.
BP6 Variant is absent from ClinVar; no reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry found for this variant.
Sources
clinvar ↗
PS5 Variant is absent from ClinVar; no reputable source has independently classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no match for this variant.
Sources
clinvar ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic 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. Details ▾Hide ▴
Evidence considered
  • Variant is intronic (-15 from exon)
  • outside canonical splice consensus
  • SpliceAI max delta 0.03 confirms no cryptic splice disruption.
Sources
pvs1_generic_framework ↗
PS1 N/AIntronic variant does not alter an amino acid; PS1 (same amino acid change as an established pathogenic variant) is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM1 N/AIntronic 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. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed in known hotspots.
PM3 N/APM3 (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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss); this is an intronic substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AIntronic variant does not produce an amino acid change; PM5 (same position, different pathogenic missense) is not applicable. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: unable to resolve amino acid residue
  • intronic variant.
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is an intronic substitution, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies specifically to missense variants in genes where truncating variants are the predominant disease mechanism. This is an intronic substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions; this is a substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies specifically to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous coding variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SH2B3
Transcript
NM_005475.2
Coding (HGVS c.)
NM_005475.2:c.835-15C>T
Protein (HGVS p.)
NP_005466.1:p.?
GRCh38
chr12:111446927 C>T
GRCh37
chr12:111884731 C>T

Gene diagram

Every interpreted variant in SH2B3, mapped onto the exon structure of NM_005475.2. Select a row to find it on the plot.

SH2B3NM_005475.2
Fetching transcript structure from UCSC…
gnomAD v4.1 29 / 1,612,940 alleles AF 1.8e-05 · 0 homozygotes · FAF 1.73e-05
gnomAD v2.1 2 / 251,006 alleles AF 7.97e-06 · 0 homozygotes · FAF 2.93e-06
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.8e-05 · 29 / 1,612,940 alleles · 0 hom · FAF 1.7e-05
European (non-Finnish)29 / 1,178,920 2.5e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,006 alleles · 0 hom · FAF 2.9e-06
European (non-Finnish)2 / 113,420 1.8e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -15 bp
0.030
SpliceAI acceptor gainat +15 bp
0.000
SpliceAI donor lossat -73 bp
0.000
SpliceAI donor gainat +44 bp
0.010
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.03 — no predicted donor gain
  • donor loss
  • acceptor gain
  • or acceptor loss above background.
Sources
spliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.03 (no predicted splicing alteration).
Sources
spliceai ↗
BP7 N/ABP7 applies specifically to synonymous variants with no predicted splice impact. This is an intronic substitution, not a synonymous coding variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 29 / 1,612,940 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).