rs1555752060

Positions:

• chr19-10985343-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.293T>C​(p.Met98Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M98I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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 2 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). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. GenCC has associacion of the 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=0.27979732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.293T>C	p.Met98Thr	missense_variant	3/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.293T>C	p.Met98Thr	missense_variant	3/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.293T>C	p.Met98Thr	missense_variant	3/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.293T>C	p.Met98Thr	missense_variant	3/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.293T>C	p.Met98Thr	missense_variant	3/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.293T>C	p.Met98Thr	missense_variant	4/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.293T>C	p.Met98Thr	missense_variant	3/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.293T>C	p.Met98Thr	missense_variant	3/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.293T>C	p.Met98Thr	missense_variant	4/35	5		ENSP00000464778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jan 02, 2017

This sequence change replaces methionine with threonine at codon 98 of the SMARCA4 protein (p.Met98Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. 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. In summary, this variant 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 C25"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;T
Eigen	Benign	0.020
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Benign	0.97	L;.;.;.;L;L;.;L;L;L;L;.;L;L;L;L;L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D;.;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;D;D
Sift4G	Benign	0.12	T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T
Polyphen		0.039	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B
Vest4		0.63
MutPred		0.32		Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);Gain of phosphorylation at M98 (P = 0.0254);
MVP		0.61
MPC		0.30
ClinPred		0.62	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.39

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: rs1555752060; hg19: chr19-11096019;