rs1291938544

Variant names:

• chr19-11010488-A-G
• rs1291938544
• NM_001387283.1:c.2231A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11010488-A-G
• chr19-11010488-A-T

Variant summary

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

The NM_003072.5(SMARCA4):​c.2231A>G​(p.Lys744Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.57

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.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2231A>G	p.Lys744Arg	missense_variant	Exon 16 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2231A>G	p.Lys744Arg	missense_variant	Exon 15 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2231A>G	p.Lys744Arg	missense_variant	Exon 16 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1643A>G	p.Lys548Arg	missense_variant	Exon 12 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.875A>G	p.Lys292Arg	missense_variant	Exon 8 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.956A>G	p.Lys319Arg	missense_variant	Exon 8 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.716A>G	p.Lys239Arg	missense_variant	Exon 7 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.584A>G	p.Lys195Arg	missense_variant	Exon 6 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Sep 11, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 744 of the SMARCA4 protein (p.Lys744Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470292). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -

not provided Uncertain:1

Jan 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K744R variant (also known as c.2231A>G), located in coding exon 14 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2231. The lysine at codon 744 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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, this variant is unlikely to be associated with rhabdoid tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Pathogenic	0.68
Sift	Benign	0.038	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.
Sift4G	Uncertain	0.058	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;D;.;.;.
Polyphen		0.88	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.
Vest4		0.36
MutPred		0.36		Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);Loss of ubiquitination at K744 (P = 0.0103);.;Loss of ubiquitination at K744 (P = 0.0103);.;.;.;
MVP		0.75
MPC		1.1
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.23
gMVP		0.69

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: rs1291938544; hg19: chr19-11121164;