19-10996519-C-A

Variant names:

• chr19-10996519-C-A
• NM_001387283.1:c.1787C>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_003072.5(SMARCA4):​c.1787C>A​(p.Thr596Lys) 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. 13/21 in silico tools predict a benign 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: 2.21

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06664896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1787C>A	p.Thr596Lys	missense_variant	Exon 12 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1787C>A	p.Thr596Lys	missense_variant	Exon 11 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1787C>A	p.Thr596Lys	missense_variant	Exon 12 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1199C>A	p.Thr400Lys	missense_variant	Exon 8 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.431C>A	p.Thr144Lys	missense_variant	Exon 4 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.512C>A	p.Thr171Lys	missense_variant	Exon 4 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.272C>A	p.Thr91Lys	missense_variant	Exon 3 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.140C>A	p.Thr47Lys	missense_variant	Exon 2 of 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

Oct 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with lysine at codon 596 of the SMARCA4 protein (p.Thr596Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Benign	0.78
DEOGEN2	Benign	0.41	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T;T;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.067	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.34	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.070	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.90	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.88	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.18	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.33
MutPred		0.31		Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);Gain of ubiquitination at T596 (P = 0.0029);.;Gain of ubiquitination at T596 (P = 0.0029);.;.;.;
MVP		0.57
MPC		1.6
ClinPred		0.54	D
GERP RS		3.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.050
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11107195;