rs1555768376

Positions:

• chr19-11003113-G-A
• chr19-11003113-G-C
• chr19-11003113-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_003072.5(SMARCA4):​c.1897G>A​(p.Ala633Thr) 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 pathogenic outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 10.0

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1897G>A	p.Ala633Thr	missense_variant	12/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1897G>A	p.Ala633Thr	missense_variant	12/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1897G>A	p.Ala633Thr	missense_variant	12/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1897G>A	p.Ala633Thr	missense_variant	12/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1897G>A	p.Ala633Thr	missense_variant	12/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1897G>A	p.Ala633Thr	missense_variant	13/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1897G>A	p.Ala633Thr	missense_variant	12/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1897G>A	p.Ala633Thr	missense_variant	12/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1897G>A	p.Ala633Thr	missense_variant	13/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1309G>A	p.Ala437Thr	missense_variant	9/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.541G>A	p.Ala181Thr	missense_variant	5/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.622G>A	p.Ala208Thr	missense_variant	5/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.382G>A	p.Ala128Thr	missense_variant	4/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.250G>A	p.Ala84Thr	missense_variant	3/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Aug 21, 2019

This sequence change replaces alanine with threonine at codon 633 of the SMARCA4 protein (p.Ala633Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMARCA4-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.4	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.70
MutPred		0.73		Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);Gain of phosphorylation at A633 (P = 0.018);.;Gain of phosphorylation at A633 (P = 0.018);.;.;.;.;
MVP		0.83
MPC		2.5
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.57
gMVP		0.78

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: rs1555768376; hg19: chr19-11113789;