rs765073845

Variant names:

• chr19-11019696-G-A
• rs765073845
• NM_001387283.1:c.2611G>A

Variant summary

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

The NM_001387283.1(SMARCA4):​c.2611G>A​(p.Ala871Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A871A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.89
• Publications: 6 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2611G>A	p.Ala871Thr	missense_variant	Exon 19 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2611G>A	p.Ala871Thr	missense_variant	Exon 18 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2611G>A	p.Ala871Thr	missense_variant	Exon 19 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2023G>A	p.Ala675Thr	missense_variant	Exon 15 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1255G>A	p.Ala419Thr	missense_variant	Exon 11 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1336G>A	p.Ala446Thr	missense_variant	Exon 11 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1096G>A	p.Ala366Thr	missense_variant	Exon 10 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.964G>A	p.Ala322Thr	missense_variant	Exon 9 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249566 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457928 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108794

Other (OTH) AF: 0.00 AC: 0 AN: 60254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000164171), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 871 of the SMARCA4 protein (p.Ala871Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 537824). 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) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA4 protein function with a positive 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

May 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A871T variant (also known as c.2611G>A), located in coding exon 17 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 2611. The alanine at codon 871 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.5	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0060	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		0.99	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.40
MutPred		0.38		Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);Gain of methylation at K876 (P = 0.0655);.;Gain of methylation at K876 (P = 0.0655);.;.;.;.;
MVP		0.88
MPC		3.2
ClinPred		0.95	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.64
gMVP		0.88
Mutation Taster		=27/73	disease causing

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: rs765073845; hg19: chr19-11130372;