chr19-11058846-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_003072.5(SMARCA4):c.4592T>A(p.Leu1531His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SMARCA4
NM_003072.5 missense
NM_003072.5 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 8.02
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 5 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). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4688T>A | p.Leu1563His | missense_variant | 33/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.4592T>A | p.Leu1531His | missense_variant | 32/35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.4598T>A | p.Leu1533His | missense_variant | 32/35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.4502T>A | p.Leu1501His | missense_variant | 32/35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.4502T>A | p.Leu1501His | missense_variant | 31/34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.4502T>A | p.Leu1501His | missense_variant | 31/34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.4499T>A | p.Leu1500His | missense_variant | 32/35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.4013T>A | p.Leu1338His | missense_variant | 29/32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.3242T>A | p.Leu1081His | missense_variant | 25/28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000644065.1 | c.3224T>A | p.Leu1075His | missense_variant | 24/27 | ENSP00000493615.1 | ||||
SMARCA4 | ENST00000642350.1 | c.3086T>A | p.Leu1029His | missense_variant | 24/27 | ENSP00000495355.1 | ||||
SMARCA4 | ENST00000643857.1 | c.2895+483T>A | intron_variant | ENSP00000494159.1 | ||||||
SMARCA4 | ENST00000538456.4 | c.699+483T>A | intron_variant | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727220
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1563 of the SMARCA4 protein (p.Leu1563His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470415). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SMARCA4 protein function with a positive predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 21, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 15, 2023 | The SMARCA4 c.4688T>A (p.Leu1563His) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2024 | The p.L1563H variant (also known as c.4688T>A), located in coding exon 32 of the SMARCA4 gene, results from a T to A substitution at nucleotide position 4688. The leucine at codon 1563 is replaced by histidine, an amino acid with similar properties. This variant has been detected in multiple individuals with no reported features of Coffin-Siris Syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.;.
Polyphen
D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Vest4
MutPred
0.81
.;.;Gain of disorder (P = 0.0412);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0412);.;.;.;.;.;
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at