chr19-10994866-C-G

Variant names:

• chr19-10994866-C-G
• rs1555762001
• NM_001387283.1:c.1458C>G

Variant summary

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

The NM_003072.5(SMARCA4):​c.1458C>G​(p.Phe486Leu) 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: 31)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.265

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1458C>G	p.Phe486Leu	missense_variant	Exon 10 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1458C>G	p.Phe486Leu	missense_variant	Exon 9 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1458C>G	p.Phe486Leu	missense_variant	Exon 10 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.870C>G	p.Phe290Leu	missense_variant	Exon 6 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.102C>G	p.Phe34Leu	missense_variant	Exon 2 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.186C>G	p.Phe62Leu	missense_variant	Exon 2 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.-55C>G		upstream_gene_variant				ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Oct 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 C15"). This variant has not been reported in the literature in individuals with SMARCA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 486 of the SMARCA4 protein (p.Phe486Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D;.
REVEL	Benign	0.17
Sift	Benign	0.23	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T;.
Sift4G	Benign	0.45	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.
Polyphen		0.16	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.
Vest4		0.61
MutPred		0.65		Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);.;
MVP		0.70
MPC		2.3
ClinPred		0.96	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		1.0

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: rs1555762001; hg19: chr19-11105542; COSMIC: COSV60789308; COSMIC: COSV60789308;