chr19-10987801-C-G

Variant names:

• chr19-10987801-C-G
• rs1013942482
• NM_001387283.1:c.995C>G

Variant summary

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

The NM_001387283.1(SMARCA4):​c.995C>G​(p.Ser332Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,686 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. S332F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.00
• Publications: 1 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=0.3408811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.995C>G	p.Ser332Cys	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.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.995C>G	p.Ser332Cys	missense_variant	Exon 7 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.995C>G	p.Ser332Cys	missense_variant	Exon 6 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.995C>G	p.Ser332Cys	missense_variant	Exon 7 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.407C>G	p.Ser136Cys	missense_variant	Exon 3 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450686 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 720894

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.00 AC: 0 AN: 85084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107528

Other (OTH) AF: 0.00 AC: 0 AN: 59858

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Mar 16, 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 cysteine, which is neutral and slightly polar, at codon 332 of the SMARCA4 protein (p.Ser332Cys). 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: 480657). 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

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S332C variant (also known as c.995C>G), located in coding exon 5 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 995. The serine at codon 332 is replaced by cysteine, 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. 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). 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	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.
PhyloP100		3.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.064	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.12	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.53
MutPred		0.23		Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);Gain of catalytic residue at S332 (P = 0.0023);
MVP		0.59
MPC		0.79
ClinPred		0.82	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.39
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1013942482; hg19: chr19-11098477;