0%
SMARCA4c.1944-1G>TLikely pathogenic
Print report
Variant interpretation report

SMARCA4 c.1944-1G>T, p.?

NM_001128849.1:c.1944-1G>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

This variant alters the canonical splice acceptor site at position -1 of intron 12 (c.1944-1G>T). SMARCA4 loss of function is an established disease mechanism for rhabdoid tumor predisposition syndrome type 2 (RTPS2). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice site variants are eligible for PVS1 at very strong weight when LOF is a confirmed disease mechanism. SpliceAI predicts a high-impact splice alteration (delta score 0.99, acceptor loss 0.99).

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the PM2 threshold for extremely low population frequency (<0.1%).

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
0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. 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.

29 criteria with recorded statuses: 2 met · 3 not met · 13 not assessed · 11 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_001128849.1:c.1944-1G>T is a canonical splice acceptor variant (c.1944-1G>T, intron 12) in SMARCA4, a gene for which loss of function is an established disease mechanism for rhabdoid tumor predisposition syndrome type 2 (RTPS2).

Under the ClinGen SVI PVS1 decision tree (PMC6185798), canonical ±1,2 splice site variants receive PVS1 at very strong strength when LOF is a confirmed disease mechanism. SpliceAI predicts a high-impact splice alteration (delta score 0.99, acceptor loss 0.99), consistent with disruption of the intron 12 splice acceptor.

The variant is absent from all queried population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion at moderate strength (<0.1% allele frequency threshold).

PP3 is not applied because the splice prediction evidence (SpliceAI) is already accounted for in the PVS1 assessment; the ClinGen SVI PVS1 guidance explicitly prohibits stacking PP3 for the same splice-effect evidence.

Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), PVS1 (Very Strong) plus PM2 (Moderate) yields a classification of Likely Pathogenic.

Met · 2

PVS1 Very strongThis variant alters the canonical splice acceptor site at position -1 of intron 12 (c.1944-1G>T). SMARCA4 loss of function is an established disease mechanism for rhabdoid tumor predisposition syndrome type 2 (RTPS2). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice site variants are eligible for PVS1 at very strong weight when LOF is a confirmed disease mechanism. SpliceAI predicts a high-impact splice alteration (delta score 0.99, acceptor loss 0.99). Details ▾Hide ▴
Evidence considered
  • Canonical splice acceptor variant at intron 12 position -1 (c.1944-1G>T)
  • SpliceAI delta score 0.99 with acceptor loss prediction 0.99
  • SMARCA4 loss of function is an established disease mechanism for RTPS2
  • ClinGen SVI PVS1 framework (PMC6185798)
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗
PM2 ModerateThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the PM2 threshold for extremely low population frequency (<0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • 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 This variant is absent from gnomAD (allele frequency 0%); it does not reach the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 allele frequency: 0%
  • gnomAD v4.1 allele frequency: 0%
  • gnomAD-Canada allele frequency: 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD (allele frequency 0%); it does not reach the BS1 benign threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 allele frequency: 0%
  • gnomAD v4.1 allele frequency: 0%
  • gnomAD-Canada allele frequency: 0%
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 Multiple computational predictors indicate a deleterious effect: SpliceAI predicts strong splice disruption (delta score 0.99, acceptor loss 0.99) and BayesDel scores 0.66, consistent with a deleterious rather than benign prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.99
  • BayesDel score 0.66 (deleterious)
Sources
spliceai ↗bayesdel

Not assessed · 13 · no assessment recorded

PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo observations reported for this variant
PS3 No well-established functional studies were identified that directly assay NM_001128849.1:c.1944-1G>T. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available
PS4 No case-control or cohort data are available to assess enriched prevalence of this variant in affected individuals. Details ▾Hide ▴
Still missing
  • No affected-individual counts or case-control data available
PM1 This variant is located at a canonical splice acceptor site (intron 12), not within a recognized SMARCA4 functional domain or mutational hotspot. Details ▾Hide ▴
Still missing
  • No hotspot or domain-level evidence applicable to this splice site
PM6 No confirmed de novo observation of NM_001128849.1:c.1944-1G>T has been reported. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No phenotype or family history data specific to this variant are available for assessment. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
PP5 This variant is absent from ClinVar and has not been classified by any reputable source. Details ▾Hide ▴
Still missing
  • No ClinVar entry or expert panel classification available
BS2 No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available
BS3 No well-established functional studies are available showing no deleterious effect for NM_001128849.1:c.1944-1G>T. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available
BS4 No cosegregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data are available to assess observation in trans with a pathogenic dominant variant. Details ▾Hide ▴
Still missing
  • No co-occurrence data available
BP5 No cases have been reported in which this variant was found together with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate-molecular-basis data available
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a splice site variant with an indeterminate protein consequence (p.?); no same-amino-acid pathogenic comparator can be established. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to recessive disorders with a second pathogenic variant in trans; SMARCA4-associated disease is dominant and no trans data are available. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-altering variants; this is a canonical splice site variant assessed under PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis is a canonical splice site variant with no defined protein residue (p.?); PM5 requires a known pathogenic missense variant at the same amino acid position. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/AThis is a splice site variant, not a missense variant; PP2 is defined for missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APer ClinGen SVI PVS1 guidance (PMC6185798), PP3 must not be stacked on top of PVS1 for the same splice-effect prediction evidence. The SpliceAI delta score of 0.99 is already accounted for in the PVS1 assessment of canonical splice disruption. Details ▾Hide ▴
Sources
pvs1_variant_assessment
BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known disease mechanism; this is a canonical splice site variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

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

No further detail was recorded.

BP6 N/AThis variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to silent variants with no predicted splice impact; NM_001128849.1:c.1944-1G>T is a canonical splice site variant with SpliceAI delta score 0.99, indicating a strong predicted splice alteration. Details ▾Hide ▴
Sources
spliceai ↗
PS5 N/AThis is a splice site variant without a defined protein-level residue; PS5 requires a pathogenic missense comparator at the same residue, which cannot be established. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SMARCA4
Transcript
NM_001128849.1
Coding (HGVS c.)
NM_001128849.1:c.1944-1G>T
Protein (HGVS p.)
NP_001122321.1:p.?
GRCh38
chr19:11003339 G>T
GRCh37
chr19:11114015 G>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 +1 bp
0.990
SpliceAI acceptor gainat -68 bp
0.650
SpliceAI donor lossat +58 bp
0.260
SpliceAI donor gainat -69 bp
0.000
Pangolin splice lossmagnitude shown
-0.880
Pangolin splice gain
0.390

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

BP4 Multiple computational predictors indicate a deleterious effect: SpliceAI predicts strong splice disruption (delta score 0.99, acceptor loss 0.99) and BayesDel scores 0.66, consistent with a deleterious rather than benign prediction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.99
  • BayesDel score 0.66 (deleterious)
Sources
spliceai ↗bayesdel
PP3 N/APer ClinGen SVI PVS1 guidance (PMC6185798), PP3 must not be stacked on top of PVS1 for the same splice-effect prediction evidence. The SpliceAI delta score of 0.99 is already accounted for in the PVS1 assessment of canonical splice disruption. Details ▾Hide ▴
Sources
pvs1_variant_assessment
BP7 N/ABP7 applies to silent variants with no predicted splice impact; NM_001128849.1:c.1944-1G>T is a canonical splice site variant with SpliceAI delta score 0.99, indicating a strong predicted splice alteration. Details ▾Hide ▴
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). 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 0.990 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 = 0.99). BayesDel score = 0.66.

Somatic

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