rs878854228
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2
The NM_003072.5(SMARCA4):c.4636-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,407,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000036 ( 0 hom. )
Consequence
SMARCA4
NM_003072.5 intron
NM_003072.5 intron
Scores
2
Splicing: ADA: 0.005246
2
Clinical Significance
Conservation
PhyloP100: 0.428
Genes affected
SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BS2
High AC in GnomAdExome4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4732-10C>A | intron_variant | ENST00000646693.2 | NP_001374212.1 | |||
SMARCA4 | NM_003072.5 | c.4636-10C>A | intron_variant | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4732-10C>A | intron_variant | NM_001387283.1 | ENSP00000495368.1 | |||||
SMARCA4 | ENST00000344626.10 | c.4636-10C>A | intron_variant | 1 | NM_003072.5 | ENSP00000343896.4 | ||||
SMARCA4 | ENST00000643549.1 | c.4642-10C>A | intron_variant | ENSP00000493975.1 | ||||||
SMARCA4 | ENST00000541122.6 | c.4546-10C>A | intron_variant | 5 | ENSP00000445036.2 | |||||
SMARCA4 | ENST00000643296.1 | c.4546-10C>A | intron_variant | ENSP00000496635.1 | ||||||
SMARCA4 | ENST00000644737.1 | c.4546-10C>A | intron_variant | ENSP00000495548.1 | ||||||
SMARCA4 | ENST00000589677.5 | c.4543-10C>A | intron_variant | 5 | ENSP00000464778.1 | |||||
SMARCA4 | ENST00000643995.1 | c.4057-10C>A | intron_variant | ENSP00000496004.1 | ||||||
SMARCA4 | ENST00000644963.1 | c.3286-10C>A | intron_variant | ENSP00000495599.1 | ||||||
SMARCA4 | ENST00000644065.1 | c.3268-10C>A | intron_variant | ENSP00000493615.1 | ||||||
SMARCA4 | ENST00000642350.1 | c.3130-10C>A | intron_variant | ENSP00000495355.1 | ||||||
SMARCA4 | ENST00000643857.1 | c.2896-10C>A | intron_variant | ENSP00000494159.1 | ||||||
SMARCA4 | ENST00000538456.4 | c.700-10C>A | intron_variant | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000355 AC: 5AN: 1407054Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2AN XY: 694826
GnomAD4 exome
AF:
AC:
5
AN:
1407054
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Cov.:
32
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AC XY:
2
AN XY:
694826
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 25, 2023 | - - |
Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
SMARCA4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 18, 2023 | The SMARCA4 c.4732-10C>A variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/537794/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 37
Find out detailed SpliceAI scores and Pangolin per-transcript scores at