0%
SMARCA4c.1813-2A>TLikely pathogenic
Print report
Variant interpretation report

SMARCA4 c.1813-2A>T, p.?

NM_001128849.1:c.1813-2A>T NP_001122321.1:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About SMARCA4

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant (position -2) in SMARCA4, a gene for which loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants are treated as null variants and qualify for PVS1 at very strong strength when the gene LoF disease mechanism is confirmed.

PM2Moderate
PM2 · moderate

NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), consistent with PM2 under generic ACMG/AMP 2015 criteria (allele frequency <0.1% in population databases).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

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

SpliceAI score
1.000 maximum delta

Recorded SpliceAI maximum delta score: 1.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied 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.

26 criteria with recorded statuses: 2 met · 3 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2 in SMARCA4, a gene where loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) [PVS1, very strong].

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0%), consistent with PM2 at moderate strength under generic ACMG/AMP 2015 criteria.

SpliceAI predicts a strong splice-disrupting effect (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but PP3 is not stacked with PVS1 per ClinGen SVI guidance (PMC6185798) to avoid double-counting the same splice-effect evidence.

This variant is absent from ClinVar and has not been reported in any publication; no external classification, functional data, segregation data, or de novo observations are available.

Under generic ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion are sufficient for a Pathogenic classification. However, transcript version discrepancy (NM_001128849.1 vs NM_001128849.3) and absence of RNA-confirmed splicing impact warrant confirmatory review.

Met · 2

PVS1 Very strongNM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant (position -2) in SMARCA4, a gene for which loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants are treated as null variants and qualify for PVS1 at very strong strength when the gene LoF disease mechanism is confirmed. Details ▾Hide ▴
Evidence considered
  • Canonical splice acceptor variant at position -2 (c.1813-2A>T)
  • SMARCA4 loss of function is an established germline disease mechanism for RTPS2 and SCCOHT
  • ClinGen SVI PVS1 framework (PMC6185798) assigns null-variant weight to canonical splice variants
Still missing
  • Transcript NM_001128849.1 has a more recent version (NM_001128849.3)
  • confirm transcript relevance
  • No RNA studies confirming aberrant splicing or NMD for this specific variant
  • Intron 11 of 35 exons — confirm biological relevance of affected exon
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), consistent with PM2 under generic ACMG/AMP 2015 criteria (allele frequency <0.1% in population databases). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles in exomes)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 3 · evaluated, threshold not reached

BA1 NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1% in population databases. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases (AF = 0%)
  • BA1 requires >1% allele frequency
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BS1 threshold of >0.3% in population databases. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases (AF = 0%)
  • BS1 requires >0.3% allele frequency
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 In silico predictions are consistent with a deleterious effect. SpliceAI predicts strong splice disruption (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score of 0.66. These results do not support BP4, which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 predicts splice-disrupting effect
  • BayesDel score 0.66 predicts damaging effect
Sources
spliceai ↗bayesdel

Not assessed · 16 · no assessment recorded

PS2 No de novo data are available for this variant. No published studies or database entries report de novo occurrence of NM_001128849.1:c.1813-2A>T with confirmed parentage. Details ▾Hide ▴
Still missing
  • No de novo observation reported in ClinVar
  • literature
  • or databases
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_001128849.1:c.1813-2A>T. No publications report functional characterization of this specific splice variant. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
PS4 No case-control or cohort data are available to assess whether the prevalence of NM_001128849.1:c.1813-2A>T is significantly increased in affected individuals versus controls. Details ▾Hide ▴
Still missing
  • No case/control or cohort prevalence data available
PM1 No mutational hotspot or critical functional domain data are available specifically for the c.1813-2 splice acceptor position in SMARCA4. Hotspot analysis did not identify this position as a recurrently mutated residue or splice site. Details ▾Hide ▴
Still missing
  • No hotspot or domain-level data for this splice acceptor position
PM6 No de novo observation of NM_001128849.1:c.1813-2A>T has been reported. No published studies or database entries describe a de novo occurrence of this variant without confirmed parentage. Details ▾Hide ▴
Still missing
  • No de novo report for this variant
PP1 No co-segregation data are available for NM_001128849.1:c.1813-2A>T with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP2 PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_001128849.1:c.1813-2A>T is a canonical splice variant, not a missense change, so PP2 is not directly applicable. Details ▾Hide ▴

No further detail was recorded.

PP4 No patient phenotype or clinical history is available for NM_001128849.1:c.1813-2A>T. PP4 requires the variant to be found in a patient with a phenotype and family history highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No phenotype data available for the proband
PP5 No reputable source has reported NM_001128849.1:c.1813-2A>T as pathogenic. The variant is absent from ClinVar, and no clinical laboratory or expert panel classification is available. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Still missing
  • No external pathogenic classification available
Sources
clinvar ↗
BS2 No data are available regarding observation of NM_001128849.1:c.1813-2A>T in healthy adults with full penetrance expected at an early age. No population or clinical cohort data address this criterion. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available
BS3 No well-established functional studies have been performed for NM_001128849.1:c.1813-2A>T demonstrating no deleterious effect on splicing or protein function. Details ▾Hide ▴
Still missing
  • No functional studies available
BS4 No segregation data are available to assess whether NM_001128849.1:c.1813-2A>T lacks segregation with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data are available regarding observation of NM_001128849.1:c.1813-2A>T in trans with a known pathogenic variant in SMARCA4. No phase information is available. Details ▾Hide ▴
Still missing
  • No trans-configuration data available
BP5 No case has been reported where NM_001128849.1:c.1813-2A>T is found in an individual with an alternative molecular basis for disease. No alternative causative variants have been documented in carriers of this variant. Details ▾Hide ▴
Still missing
  • No data on co-occurrence with alternative molecular diagnoses
BP6 No reputable source has reported NM_001128849.1:c.1813-2A>T as benign or likely benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Still missing
  • No external benign classification available
Sources
clinvar ↗
PS5 No reputable source (e.g., clinical laboratory, research consortium) has reported NM_001128849.1:c.1813-2A>T as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Still missing
  • No external classification of this variant available
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a different nucleotide change at the same codon predicted to produce the same missense change. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant, not a missense substitution, so PS1 does not apply. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants where a different amino acid substitution at the same residue has been established as pathogenic. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant with an unknown protein consequence (p.?), and no residue-level comparator can be determined. Details ▾Hide ▴
Evidence considered
  • Canonical splice variant
  • no protein residue context available for PM5
Sources
pm5_candidates
PP3 N/AUnder ClinGen SVI PVS1 guidance (PMC6185798), PP3 (in silico prediction of pathogenicity) should not be stacked with PVS1 when the in silico evidence supports the same splice-effect prediction already captured by PVS1. SpliceAI predicts a deleterious effect (max delta 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but this evidence is redundant with PVS1 and is not independently applied to avoid double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 (DS_AL=1.0
  • DS_AG=0.89) — consistent with splice disruption
  • BayesDel score 0.66 — predicted damaging
  • PMC6185798 prohibits stacking PP3 with PVS1 for the same splice-effect evidence
Sources
spliceai ↗bayesdelpvs1_generic_framework ↗
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. NM_001128849.1:c.1813-2A>T is a canonical splice variant, not a missense substitution, so BP1 does not apply. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2, not a synonymous coding variant, so BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SMARCA4
Transcript
NM_001128849.1
Coding (HGVS c.)
NM_001128849.1:c.1813-2A>T
Protein (HGVS p.)
NP_001122321.1:p.?
GRCh38
chr19:11003027 A>T
GRCh37
chr19:11113703 A>T

Gene diagram

Every interpreted variant in SMARCA4, mapped onto the exon structure of NM_001128849.1. Select a row to find it on the plot.

SMARCA4NM_001128849.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp
1.000
SpliceAI acceptor gainat +19 bp
0.890
SpliceAI donor lossat +132 bp
0.020
SpliceAI donor gainat +43 bp
0.000
Pangolin splice lossmagnitude shown
-0.870
Pangolin splice gain
0.670

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

BP4 In silico predictions are consistent with a deleterious effect. SpliceAI predicts strong splice disruption (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score of 0.66. These results do not support BP4, which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 predicts splice-disrupting effect
  • BayesDel score 0.66 predicts damaging effect
Sources
spliceai ↗bayesdel
PP3 N/AUnder ClinGen SVI PVS1 guidance (PMC6185798), PP3 (in silico prediction of pathogenicity) should not be stacked with PVS1 when the in silico evidence supports the same splice-effect prediction already captured by PVS1. SpliceAI predicts a deleterious effect (max delta 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but this evidence is redundant with PVS1 and is not independently applied to avoid double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 1.0 (DS_AL=1.0
  • DS_AG=0.89) — consistent with splice disruption
  • BayesDel score 0.66 — predicted damaging
  • PMC6185798 prohibits stacking PP3 with PVS1 for the same splice-effect evidence
Sources
spliceai ↗bayesdelpvs1_generic_framework ↗
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2, not a synonymous coding variant, so BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.

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 Recorded maximum delta 1.000 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.

Somatic

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