19-11007902-G-C

Variant names:

• chr19-11007902-G-C
• rs1060502105
• NM_001387283.1:c.2002G>C

Variant summary

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

The NM_001387283.1(SMARCA4):​c.2002G>C​(p.Glu668Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. E668K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense, splice_region
• Scores: Splicing: ADA: 0.9957
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.37
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, 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.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 15 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 14 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2002G>C	p.Glu668Gln	missense_variant, splice_region_variant	Exon 15 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1414G>C	p.Glu472Gln	missense_variant, splice_region_variant	Exon 11 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.646G>C	p.Glu216Gln	missense_variant, splice_region_variant	Exon 7 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.727G>C	p.Glu243Gln	missense_variant, splice_region_variant	Exon 7 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.487G>C	p.Glu163Gln	missense_variant, splice_region_variant	Exon 6 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.355G>C	p.Glu119Gln	missense_variant, splice_region_variant	Exon 5 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458794 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725708

African (AFR) AF: 0.0000599 AC: 2 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110032

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 31

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

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 668 of the SMARCA4 protein (p.Glu668Gln). 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: 820520). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E668Q variant (also known as c.2002G>C) is located in coding exon 13 of the SMARCA4 gene. The glutamic acid at codon 668 is replaced by glutamine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 13. This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however, RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. 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, 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	0.33
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.077	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.077	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Vest4		0.45
ClinPred		0.87	D
GERP RS		4.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.0
Varity_R		0.13
gMVP		0.61
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 3

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

Other links and lift over

dbSNP: rs1060502105; hg19: chr19-11118578;