19-11059851-G-C

Position:

• chr19-11059851-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_003072.5(SMARCA4):​c.4734G>C​(p.Glu1578Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.549

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. 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=0.06443444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4830G>C	p.Glu1610Asp	missense_variant	34/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4734G>C	p.Glu1578Asp	missense_variant	33/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4830G>C	p.Glu1610Asp	missense_variant	34/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4734G>C	p.Glu1578Asp	missense_variant	33/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4740G>C	p.Glu1580Asp	missense_variant	33/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4644G>C	p.Glu1548Asp	missense_variant	33/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4644G>C	p.Glu1548Asp	missense_variant	32/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4644G>C	p.Glu1548Asp	missense_variant	32/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4641G>C	p.Glu1547Asp	missense_variant	33/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4155G>C	p.Glu1385Asp	missense_variant	30/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3384G>C	p.Glu1128Asp	missense_variant	26/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3366G>C	p.Glu1122Asp	missense_variant	25/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3228G>C	p.Glu1076Asp	missense_variant	25/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2994G>C	p.Glu998Asp	missense_variant	23/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.798G>C	p.Glu266Asp	missense_variant	6/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2017

The p.E1610D variant (also known as c.4830G>C), located in coding exon 33 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 4830. The glutamic acid at codon 1610 is replaced by aspartic acid, an amino acid with highly 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	0.076
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	.;T;.;.;.;.;T;.;.;.;D;.;T;T;T;T;D;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.064	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.29	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.33	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.69	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.0050	B;.;P;.;.;.;.;.;.;.;B;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.30
MutPred		0.094		.;.;Loss of helix (P = 0.1299);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.1299);.;.;.;.;
MVP		0.64
MPC		0.90
ClinPred		0.056	T
GERP RS		-0.55
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.12
gMVP		0.70

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.

Other links and lift over

hg19: chr19-11170527;