rs1060502077

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001387283.1(SMARCA4):c.44G>A(p.Gly15Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.44G>A	p.Gly15Asp	missense_variant	2/36	ENST00000646693.2
SMARCA4	NM_003072.5 linkuse as main transcript	c.44G>A	p.Gly15Asp	missense_variant	2/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.44G>A	p.Gly15Asp	missense_variant	2/36		NM_001387283.1
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.44G>A	p.Gly15Asp	missense_variant	2/35	1	NM_003072.5	P4	P51532-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Apr 30, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 15 of the SMARCA4 protein (p.Gly15Asp). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The p.G15D variant (also known as c.44G>A), located in coding exon 1 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 44. The glycine at codon 15 is replaced by aspartic acid, an amino acid with similar properties. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.1

L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.8

D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0070

D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D

Sift4G

Uncertain

0.032

D;.;.;.;.;.;.;.;.;.;D;.;.;D;D;D;D;D;D

Polyphen

0.98

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D

Vest4

0.76

MutPred

0.15

Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);Loss of glycosylation at P20 (P = 0.1896);

MVP

0.89

MPC

0.33

ClinPred

0.94

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.29

gMVP

0.65

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over