chr19-11033783-C-A

Position:

• chr19-11033783-C-A

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.3791C>A​(p.Thr1264Lys) 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. 12/21 in silico tools predict 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. T1264M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.76

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=0.1847601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3791C>A	p.Thr1264Lys	missense_variant	27/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3791C>A	p.Thr1264Lys	missense_variant	27/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3791C>A	p.Thr1264Lys	missense_variant	27/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3791C>A	p.Thr1264Lys	missense_variant	27/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643995.1	c.3203C>A	p.Thr1068Lys	missense_variant	24/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2435C>A	p.Thr812Lys	missense_variant	20/28			ENSP00000495599.1
SMARCA4	ENST00000642350.1	c.2276C>A	p.Thr759Lys	missense_variant	19/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2144C>A	p.Thr715Lys	missense_variant	18/25			ENSP00000494159.1
SMARCA4	ENST00000643549.1	c.3774+266C>A		intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3774+266C>A		intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3774+266C>A		intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3774+266C>A		intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3774+266C>A		intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000644065.1	c.2499+266C>A		intron_variant				ENSP00000493615.1
SMARCA4	ENST00000538456.4	c.30+266C>A		intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2021

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 with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 1264 of the SMARCA4 protein (p.Thr1264Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The p.T1264K variant (also known as c.3791C>A), located in coding exon 26 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 3791. The threonine at codon 1264 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;T;T;.;.
Eigen	Benign	-0.046
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;.;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.075	N;.;N;.;.;.
MutationTaster	Benign	0.77	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.57	N;.;N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.12	T;.;T;.;.;.
Sift4G	Benign	0.30	T;.;T;T;.;.
Polyphen		0.063	B;B;B;B;.;.
Vest4		0.30
MutPred		0.28		Gain of ubiquitination at T1264 (P = 0.0042);Gain of ubiquitination at T1264 (P = 0.0042);Gain of ubiquitination at T1264 (P = 0.0042);Gain of ubiquitination at T1264 (P = 0.0042);.;.;
MVP		0.68
MPC		1.7
ClinPred		0.62	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.71

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: rs377119410; hg19: chr19-11144459;