19-11041343-G-A

Position:

• chr19-11041343-G-A

Variant summary

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

The NM_003072.5(SMARCA4):​c.4207G>A​(p.Glu1403Lys) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.95

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.4303G>A	p.Glu1435Lys	missense_variant	31/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4207G>A	p.Glu1403Lys	missense_variant	30/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4303G>A	p.Glu1435Lys	missense_variant	31/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4207G>A	p.Glu1403Lys	missense_variant	30/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4213G>A	p.Glu1405Lys	missense_variant	30/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4117G>A	p.Glu1373Lys	missense_variant	30/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4117G>A	p.Glu1373Lys	missense_variant	29/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4117G>A	p.Glu1373Lys	missense_variant	29/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4117G>A	p.Glu1373Lys	missense_variant	30/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3628G>A	p.Glu1210Lys	missense_variant	27/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2860G>A	p.Glu954Lys	missense_variant	23/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2842G>A	p.Glu948Lys	missense_variant	22/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2701G>A	p.Glu901Lys	missense_variant	22/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2569G>A	p.Glu857Lys	missense_variant	21/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.373G>A	p.Glu125Lys	missense_variant	4/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2015

In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change replaces glutamic acid with lysine at codon 1435 of the SMARCA4 protein (p.Glu1435Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The p.E1435K variant (also known as c.4303G>A), located in coding exon 30 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4303. The glutamic acid at codon 1435 is replaced by lysine, an amino acid with similar properties. 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). 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 supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.34	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.33	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.40	B;.;P;.;.;.;.;.;.;.;B;.;.;.;.;.;.;P;.;.;.;.;.
Vest4		0.84
MutPred		0.37		.;.;Gain of methylation at E1435 (P = 0.0022);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of methylation at E1435 (P = 0.0022);.;.;.;.;.;
MVP		0.81
MPC		1.4
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.38
gMVP		0.89

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: rs878854223; hg19: chr19-11152019;