chr19-11061787-C-A

Variant names:

• chr19-11061787-C-A
• rs776222414
• NM_001387283.1:c.5011C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001387283.1(SMARCA4):​c.5011C>A​(p.Arg1671Ser) 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. R1671H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5011C>A	p.Arg1671Ser	missense_variant	Exon 36 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4915C>A	p.Arg1639Ser	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.5011C>A	p.Arg1671Ser	missense_variant	Exon 36 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4915C>A	p.Arg1639Ser	missense_variant	Exon 35 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4921C>A	p.Arg1641Ser	missense_variant	Exon 35 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4825C>A	p.Arg1609Ser	missense_variant	Exon 35 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4825C>A	p.Arg1609Ser	missense_variant	Exon 34 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4825C>A	p.Arg1609Ser	missense_variant	Exon 34 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4822C>A	p.Arg1608Ser	missense_variant	Exon 35 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4336C>A	p.Arg1446Ser	missense_variant	Exon 32 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3565C>A	p.Arg1189Ser	missense_variant	Exon 28 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3547C>A	p.Arg1183Ser	missense_variant	Exon 27 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3409C>A	p.Arg1137Ser	missense_variant	Exon 27 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3175C>A	p.Arg1059Ser	missense_variant	Exon 25 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.979C>A	p.Arg327Ser	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 09, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1671S variant (also known as c.5011C>A), located in coding exon 35 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 5011. The arginine at codon 1671 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;D;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.080	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.018	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.
Sift4G	Benign	0.62	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.034	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.37
MutPred		0.17		.;.;Gain of phosphorylation at R1671 (P = 2e-04);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at R1671 (P = 2e-04);.;.;.;
MVP		0.67
MPC		1.1
ClinPred		0.80	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.67
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776222414; hg19: chr19-11172463;