rs1060502099

Positions:

• chr19-11059819-G-A
• chr19-11059819-G-C
• chr19-11059819-G-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.4702G>A​(p.Asp1568Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

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 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=0.1843785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4798G>A	p.Asp1600Asn	missense_variant	34/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4702G>A	p.Asp1568Asn	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.4798G>A	p.Asp1600Asn	missense_variant	34/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4702G>A	p.Asp1568Asn	missense_variant	33/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4708G>A	p.Asp1570Asn	missense_variant	33/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4612G>A	p.Asp1538Asn	missense_variant	33/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4612G>A	p.Asp1538Asn	missense_variant	32/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4612G>A	p.Asp1538Asn	missense_variant	32/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4609G>A	p.Asp1537Asn	missense_variant	33/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4123G>A	p.Asp1375Asn	missense_variant	30/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3352G>A	p.Asp1118Asn	missense_variant	26/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3334G>A	p.Asp1112Asn	missense_variant	25/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3196G>A	p.Asp1066Asn	missense_variant	25/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2962G>A	p.Asp988Asn	missense_variant	23/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.766G>A	p.Asp256Asn	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

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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 aspartic acid with asparagine at codon 1600 of the SMARCA4 protein (p.Asp1600Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.0055
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.075
Sift	Benign	0.098	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.41	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.22
MutPred		0.11		.;.;Gain of helix (P = 0.132);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of helix (P = 0.132);.;.;.;.;
MVP		0.51
MPC		0.96
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.81

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: rs1060502099; hg19: chr19-11170495; COSMIC: COSV60790414; COSMIC: COSV60790414;