About SH2B3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SH2B3 c.*2C>T, p.?
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; combination = 1 supporting, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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 ↗
No screenshot for this evidence
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 14 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The SH2B3 c.*2C>T (NP_005466.1:p.?) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the usual PM2 threshold of 0.001 (0.1%).
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.
In silico splice prediction does not support a splice-altering effect, with a SpliceAI maximum delta score of 0.04.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2 supports pathogenicity when a variant is absent or at extremely low frequency in population databases.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 5 · evaluated, threshold not reached
PS4 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. Details ▾Hide ▴
Rule
PS4 requires statistically increased prevalence in affected individuals compared with controls.
Evidence considered
- ClinVar search found no result for this variant.
Still missing
- Affected-versus-control enrichment data would be needed to support PS4.
Sources
PP3 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. Details ▾Hide ▴
Rule
PP3 requires multiple computational predictions supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.04.
- DS_AG 0.01
- DS_AL 0.04
- DS_DG 0.00
- DS_DL 0.01.
- No REVEL or BayesDel score was available for this variant.
Still missing
- Additional validated regulatory prediction or functional evidence would be needed to assess non-splice 3'UTR effects.
Sources
BA1 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. Details ▾Hide ▴
Rule
BA1 applies when population frequency is greater than 1%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 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. Details ▾Hide ▴
Rule
BS1 applies when allele frequency is greater than expected for the disorder.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 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. Details ▾Hide ▴
Rule
BP4 requires computational evidence supporting no impact on the gene or gene product.
Evidence considered
- SpliceAI max delta score 0.04.
Still missing
- Additional validated benign computational or functional evidence addressing 3'UTR regulatory impact would be needed.
Sources
Not assessed · 14 · no assessment recorded
PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history.
Still missing
- Confirmed de novo occurrence data are needed.
PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies supportive of a damaging effect.
Still missing
- Validated functional studies for NM_005475.2:c.*2C>T are needed.
PM1 No established mutational hotspot or well-characterized critical functional region supporting PM1 at this 3'UTR position was identified. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
Still missing
- Variant-specific hotspot or critical-region evidence is needed.
PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 requires detection in trans with a pathogenic variant for a recessive disorder.
Still missing
- Phase and recessive case data are needed.
PM6 No assumed de novo occurrence data were identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Rule
PM6 requires an assumed, but not confirmed, de novo occurrence.
Still missing
- Assumed de novo data are needed.
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Still missing
- Family segregation data are needed.
PP4 No phenotype-specific evidence was identified showing a clinical presentation highly specific for a disorder caused by this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Still missing
- Detailed phenotype and differential-diagnosis data are needed.
PP5 No pathogenic assertion from a reputable source was identified for this variant, so PP5 was not assessed. Details ▾Hide ▴
Rule
PP5 concerns pathogenic assertions from a reputable source without available primary evidence.
Evidence considered
- ClinVar search found no result for this variant.
Sources
BS2 No direct evidence was identified showing this variant in healthy adult individuals in a context appropriate for BS2, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adult individuals for a disorder with expected full penetrance at an early age.
Still missing
- Confirmed observation in healthy adults for the relevant disease context is needed.
BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Still missing
- Validated benign functional evidence for NM_005475.2:c.*2C>T is needed.
BS4 No family studies showing lack of cosegregation with disease were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in affected family members.
Still missing
- Family segregation data demonstrating lack of cosegregation are needed.
BP2 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. Details ▾Hide ▴
Rule
BP2 requires phase information with another pathogenic variant.
Still missing
- Phase data are needed.
BP5 No alternate molecular explanation for the reported phenotype was identified from the available evidence, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 requires a variant found in a case with an alternate molecular basis for disease.
Still missing
- A confirmed alternative cause of disease would be needed.
BP6 No benign assertion from a reputable source was identified for this variant, so BP6 was not assessed. Details ▾Hide ▴
Rule
BP6 concerns benign assertions from a reputable source without available primary evidence.
Evidence considered
- ClinVar search found no result for this variant.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AAlthough 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. Details ▾Hide ▴
Rule
Generic PVS1 fallback applies only to eligible loss-of-function variant classes.
Evidence considered
- SH2B3 loss of function is supported as a disease mechanism at the gene level.
- NM_005475.2:c.*2C>T is a 3'UTR substitution in the variant_bucket 'other'.
- apply_generic_pvs1_framework is false.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗3299048337981895303333053257160432581363
PS1 N/APS1 is not applicable because this 3'UTR variant does not create the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a known pathogenic variant.
Evidence considered
- Variant consequence is noncoding 3'UTR.
PM4 N/APM4 is not applicable because this variant does not change protein length and is located in the 3'UTR. Details ▾Hide ▴
Rule
PM4 applies to protein length changes such as in-frame insertions/deletions or stop-loss variants.
Evidence considered
- Variant consequence is noncoding 3'UTR.
PM5 N/APM5 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. Details ▾Hide ▴
Rule
PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense variant has been established.
Evidence considered
- Variant consequence is noncoding 3'UTR.
PP2 N/APP2 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
PP2 is a missense-specific criterion.
Evidence considered
- Variant consequence is noncoding 3'UTR.
BP1 N/ABP1 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
BP1 is a missense-specific criterion.
Evidence considered
- Variant consequence is noncoding 3'UTR.
BP3 N/ABP3 is not applicable because this is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Rule
BP3 applies to certain in-frame insertions/deletions in repetitive regions without known function.
Evidence considered
- Variant consequence is a single-nucleotide 3'UTR substitution.
BP7 N/ABP7 is not applicable because this variant is not a synonymous or intronic change outside splice regions; it is a 3'UTR substitution. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splice impact.
Evidence considered
- Variant consequence is noncoding 3'UTR.
Identifiers
- Gene
- SH2B3
- Transcript
- NM_005475.2
- Coding (HGVS c.)
- NM_005475.2:c.*2C>T
- Protein (HGVS p.)
- NP_005466.1:p.?
- GRCh38
- chr12:111448304 C>T
- GRCh37
- chr12:111886108 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…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in SH2B3
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 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. Details ▾Hide ▴
Rule
PP3 requires multiple computational predictions supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.04.
- DS_AG 0.01
- DS_AL 0.04
- DS_DG 0.00
- DS_DL 0.01.
- No REVEL or BayesDel score was available for this variant.
Still missing
- Additional validated regulatory prediction or functional evidence would be needed to assess non-splice 3'UTR effects.
Sources
BP4 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. Details ▾Hide ▴
Rule
BP4 requires computational evidence supporting no impact on the gene or gene product.
Evidence considered
- SpliceAI max delta score 0.04.
Still missing
- Additional validated benign computational or functional evidence addressing 3'UTR regulatory impact would be needed.
Sources
BP7 N/ABP7 is not applicable because this variant is not a synonymous or intronic change outside splice regions; it is a 3'UTR substitution. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splice impact.
Evidence considered
- Variant consequence is noncoding 3'UTR.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005475.2%3Ac.%2A2C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-111886108-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-111448304-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005475.2%3Ac.%2A2…
- OncoKB ↗www.oncokb.org/gene/SH2B3/?
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).