NM_001387283.1:c.313G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001387283.1(SMARCA4):​c.313G>T​(p.Gly105Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G105R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.90

Publications

0 publications found
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]
SMARCA4 Gene-Disease associations (from GenCC):
  • Coffin-Siris syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
  • intellectual disability, autosomal dominant 16
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • rhabdoid tumor predisposition syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
  • uterine corpus sarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • familial rhabdoid tumor
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 35 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.313G>T p.Gly105Trp missense_variant Exon 4 of 35 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.313G>T p.Gly105Trp missense_variant Exon 3 of 34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.313G>T p.Gly105Trp missense_variant Exon 4 of 35 5 ENSP00000464778.1 P51532-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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
Aug 04, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.G105W variant (also known as c.313G>T), located in coding exon 2 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 313. The glycine at codon 105 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Benign
1.1
L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PhyloP100
9.9
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-3.2
D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G
Benign
0.073
T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;D;T
Polyphen
1.0
D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D
Vest4
0.72
MutPred
0.30
Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);Gain of MoRF binding (P = 0.0343);
MVP
0.91
MPC
0.98
ClinPred
0.98
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.46
gMVP
0.53
Mutation Taster
=10/90
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1060502074; hg19: chr19-11096039; API