rs1366085446
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP6
The NM_003072.5(SMARCA4):c.259G>A(p.Asp87Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SMARCA4
NM_003072.5 missense
NM_003072.5 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 9.96
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 2 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.
BP6
Variant 19-10985309-G-A is Benign according to our data. Variant chr19-10985309-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 941120.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.259G>A | p.Asp87Asn | missense_variant | 3/36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.259G>A | p.Asp87Asn | missense_variant | 3/35 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.259G>A | p.Asp87Asn | missense_variant | 3/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.259G>A | p.Asp87Asn | missense_variant | 3/35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.259G>A | p.Asp87Asn | missense_variant | 3/35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.259G>A | p.Asp87Asn | missense_variant | 4/35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.259G>A | p.Asp87Asn | missense_variant | 3/34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.259G>A | p.Asp87Asn | missense_variant | 3/34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.259G>A | p.Asp87Asn | missense_variant | 4/35 | 5 | ENSP00000464778.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727204
GnomAD4 exome
AF:
AC:
2
AN:
1461812
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727204
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 08, 2023 | This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 941120). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 87 of the SMARCA4 protein (p.Asp87Asn). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G
Benign
T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen
P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P
Vest4
MutPred
Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);Gain of MoRF binding (P = 0.0379);
MVP
MPC
0.76
ClinPred
D
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