rs373041389

Positions:

• chr19-11034143-C-A
• chr19-11034143-C-G
• chr19-11034143-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.3894C>A​(p.Asp1298Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: -1.73

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 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	Protein	UniProt
SMARCA4	NM_001387283.1	c.3894C>A	p.Asp1298Glu	missense_variant	28/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3894C>A	p.Asp1298Glu	missense_variant	28/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3894C>A	p.Asp1298Glu	missense_variant	28/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3894C>A	p.Asp1298Glu	missense_variant	28/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3795C>A	p.Asp1265Glu	missense_variant	27/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3795C>A	p.Asp1265Glu	missense_variant	28/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3795C>A	p.Asp1265Glu	missense_variant	27/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3795C>A	p.Asp1265Glu	missense_variant	27/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3795C>A	p.Asp1265Glu	missense_variant	28/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3306C>A	p.Asp1102Glu	missense_variant	25/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2538C>A	p.Asp846Glu	missense_variant	21/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2520C>A	p.Asp840Glu	missense_variant	20/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2379C>A	p.Asp793Glu	missense_variant	20/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2247C>A	p.Asp749Glu	missense_variant	19/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.51C>A	p.Asp17Glu	missense_variant	2/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jun 08, 2017

The p.D1298E variant (also known as c.3894C>A), located in coding exon 27 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 3894. The aspartic acid at codon 1298 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	1.5
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.035
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.58
MutPred		0.30		Loss of phosphorylation at T1301 (P = 0.217);.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;.;.;.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;.;.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;
MVP		0.89
MPC		2.6
ClinPred		0.96	D
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.40
gMVP		0.84

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: rs373041389; hg19: chr19-11144819;