rs939033260

Variant names:

• chr19-10996215-T-A
• rs939033260
• NM_001387283.1:c.1596T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10996215-T-A
• chr19-10996215-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387283.1(SMARCA4):​c.1596T>A​(p.Ala532Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A532A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 11 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 10 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1596T>A	p.Ala532Ala	splice_region_variant, synonymous_variant	Exon 11 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1008T>A	p.Ala336Ala	splice_region_variant, synonymous_variant	Exon 7 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.240T>A	p.Ala80Ala	splice_region_variant, synonymous_variant	Exon 3 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.324T>A	p.Ala108Ala	splice_region_variant, synonymous_variant	Exon 3 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.84T>A	p.Ala28Ala	splice_region_variant, synonymous_variant	Exon 2 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.-52T>A		upstream_gene_variant				ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.5
DANN	Benign	0.82
PhyloP100		-0.56
PromoterAI		-0.0031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 2

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

Other links and lift over

dbSNP: rs939033260; hg19: chr19-11106891;