19-10987698-A-G

Variant names:

• chr19-10987698-A-G
• rs878854244
• NM_001387283.1:c.892A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001387283.1(SMARCA4):​c.892A>G​(p.Thr298Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. T298I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.493
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04820937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.892A>G	p.Thr298Ala	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.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.892A>G	p.Thr298Ala	missense_variant	Exon 7 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.892A>G	p.Thr298Ala	missense_variant	Exon 6 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.892A>G	p.Thr298Ala	missense_variant	Exon 7 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.304A>G	p.Thr102Ala	missense_variant	Exon 3 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Jan 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces threonine with alanine at codon 298 of the SMARCA4 protein (p.Thr298Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Hereditary cancer-predisposing syndrome Uncertain:1

May 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T298A variant (also known as c.892A>G), located in coding exon 5 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 892. The threonine at codon 298 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.57
DEOGEN2	Benign	0.24	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.81	.;T;.;.;.;.;T;.;.;.;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.048	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.35	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.
PhyloP100		0.49
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.25	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.64	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.64	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B
Vest4		0.20
MutPred		0.14		Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);Loss of phosphorylation at T298 (P = 0.0065);
MVP		0.44
MPC		0.25
ClinPred		0.046	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.033
gMVP		0.050
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs878854244; hg19: chr19-11098374;