rs1555755346

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_003072.5(SMARCA4):​c.1117A>G​(p.Arg373Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_003072.5 missense, splice_region

Scores

10
5
4
Splicing: ADA: 0.9956
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.10
Variant links:
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). 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/351 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 7/355 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 6/34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkuse as main transcriptc.1117A>G p.Arg373Gly missense_variant, splice_region_variant 7/355 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkuse as main transcriptc.529A>G p.Arg177Gly missense_variant, splice_region_variant 3/32 ENSP00000496004.1 A0A2R8YGG3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 19, 2017In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMARCA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 373 of the SMARCA4 protein (p.Arg373Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Benign
2.0
M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.3
D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.11
T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G
Benign
0.30
T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen
0.97
D;.;P;.;.;.;.;.;.;.;D;.;.;.;.;.;.;P
Vest4
0.96
MutPred
0.46
Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);Loss of MoRF binding (P = 0.0221);
MVP
0.92
MPC
2.5
ClinPred
0.99
D
GERP RS
4.5
Varity_R
0.71
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.76
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.76
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555755346; hg19: chr19-11098599; API