rs886054151

Variant names:

• chr19-10987774-C-T
• rs886054151
• NM_001387283.1:c.968C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387283.1(SMARCA4):​c.968C>T​(p.Ser323Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S323A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.52
• Publications: 2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39523318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.968C>T	p.Ser323Leu	missense_variant	Exon 7 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.968C>T	p.Ser323Leu	missense_variant	Exon 6 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.968C>T	p.Ser323Leu	missense_variant	Exon 7 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.380C>T	p.Ser127Leu	missense_variant	Exon 3 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000476 AC: 1 AN: 210270 AF XY: 0.00000863

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446664 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 718428

African (AFR) AF: 0.00 AC: 0 AN: 33122

American (AMR) AF: 0.00 AC: 0 AN: 43070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 38908

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50442

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105336

Other (OTH) AF: 0.00 AC: 0 AN: 59648

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 323 of the SMARCA4 protein (p.Ser323Leu). 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: 328022). 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) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S323L variant (also known as c.968C>T), located in coding exon 5 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 968. The serine at codon 323 is replaced by leucine, an amino acid with dissimilar properties. 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 available evidence, the clinical significance of this variant remains unclear. -

Coffin-Siris syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Benign	1.9	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PhyloP100		3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.058	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.14	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.83	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D
Vest4		0.59
MutPred		0.18		Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);Loss of glycosylation at S323 (P = 0.0044);
MVP		0.79
MPC		0.29
ClinPred		0.68	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.18
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886054151; hg19: chr19-11098450; COSMIC: COSV106061923;