rs201600949
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_003072.5(SMARCA4):c.719C>A(p.Pro240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SMARCA4
NM_003072.5 missense
NM_003072.5 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 1.32
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.118052185).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.719C>A | p.Pro240Gln | missense_variant | 4/36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.719C>A | p.Pro240Gln | missense_variant | 4/35 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.719C>A | p.Pro240Gln | missense_variant | 4/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.719C>A | p.Pro240Gln | missense_variant | 4/35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.719C>A | p.Pro240Gln | missense_variant | 4/35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.719C>A | p.Pro240Gln | missense_variant | 5/35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.719C>A | p.Pro240Gln | missense_variant | 4/34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.719C>A | p.Pro240Gln | missense_variant | 4/34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.719C>A | p.Pro240Gln | missense_variant | 5/35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.131C>A | p.Pro44Gln | missense_variant | 1/32 | ENSP00000496004.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1386750Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 684462
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1386750
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
684462
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 NFE exome
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Gnomad4 OTH exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The p.P240Q variant (also known as c.719C>A), located in coding exon 3 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 719. The proline at codon 240 is replaced by glutamine, an amino acid with similar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G
Benign
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen
P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P
Vest4
MutPred
Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);Loss of glycosylation at P240 (P = 0.0252);
MVP
MPC
0.24
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at