19-10984272-A-G

Position:

• chr19-10984272-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000344626.10(SMARCA4):​c.121A>G​(p.Ser41Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. S41I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 ENST00000344626.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19276991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.121A>G	p.Ser41Gly	missense_variant	2/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.121A>G	p.Ser41Gly	missense_variant	2/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.121A>G	p.Ser41Gly	missense_variant	2/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10	c.121A>G	p.Ser41Gly	missense_variant	2/35	1	NM_003072.5	ENSP00000343896	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 41 of the SMARCA4 protein (p.Ser41Gly). 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: 480692). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function. 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	Aug 16, 2023	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2017

The p.S41G variant (also known as c.121A>G), located in coding exon 1 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 121. The serine at codon 41 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.078
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
MutationTaster	Benign	0.82	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.75	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.027	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.29	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4		0.30
MutPred		0.074		Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);Loss of phosphorylation at S41 (P = 0.0046);
MVP		0.64
MPC		0.23
ClinPred		0.60	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1555750818; hg19: chr19-11094948; COSMIC: COSV100758727; COSMIC: COSV100758727;