19-11061788-G-T

Variant names:

• chr19-11061788-G-T
• rs867536416
• NM_001387283.1:c.5012G>T

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.4916G>T​(p.Arg1639Leu) variant causes a missense change. 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. R1639H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.13

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 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=0.19212514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5012G>T	p.Arg1671Leu	missense_variant	Exon 36 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4916G>T	p.Arg1639Leu	missense_variant	Exon 35 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.5012G>T	p.Arg1671Leu	missense_variant	Exon 36 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4916G>T	p.Arg1639Leu	missense_variant	Exon 35 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4922G>T	p.Arg1641Leu	missense_variant	Exon 35 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4826G>T	p.Arg1609Leu	missense_variant	Exon 35 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4826G>T	p.Arg1609Leu	missense_variant	Exon 34 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4826G>T	p.Arg1609Leu	missense_variant	Exon 34 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4823G>T	p.Arg1608Leu	missense_variant	Exon 35 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4337G>T	p.Arg1446Leu	missense_variant	Exon 32 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3566G>T	p.Arg1189Leu	missense_variant	Exon 28 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3548G>T	p.Arg1183Leu	missense_variant	Exon 27 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3410G>T	p.Arg1137Leu	missense_variant	Exon 27 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3176G>T	p.Arg1059Leu	missense_variant	Exon 25 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.980G>T	p.Arg327Leu	missense_variant	Exon 8 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1671 of the SMARCA4 protein (p.Arg1671Leu). 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: 565470). Advanced 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 at Invitae 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1671L variant (also known as c.5012G>T), located in coding exon 35 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 5012. The arginine at codon 1671 is replaced by leucine, an amino acid with dissimilar properties. 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). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.028
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0080	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.
Sift4G	Benign	0.20	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.034	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.43
MutPred		0.13		.;.;Gain of helix (P = 0.0425);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of helix (P = 0.0425);.;.;.;
MVP		0.92
MPC		1.2
ClinPred		0.76	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
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: rs867536416; hg19: chr19-11172464;