NM_001387283.1:c.2653C>A

Variant names:

• chr19-11021761-C-A
• rs281875227
• NM_001387283.1:c.2653C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001387283.1(SMARCA4):​c.2653C>A​(p.Arg885Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 2.53
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001387283.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11021762-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 420093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	NM_001387283.1	MANE Plus Clinical	c.2653C>A	p.Arg885Ser	missense	Exon 19 of 36	NP_001374212.1
	SMARCA4	NM_003072.5	MANE Select	c.2653C>A	p.Arg885Ser	missense	Exon 19 of 35	NP_003063.2
	SMARCA4	NM_001128849.3		c.2653C>A	p.Arg885Ser	missense	Exon 19 of 36	NP_001122321.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.2653C>A	p.Arg885Ser	missense	Exon 19 of 36	ENSP00000495368.1
	SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.2653C>A	p.Arg885Ser	missense	Exon 19 of 35	ENSP00000343896.4
	SMARCA4	ENST00000643549.1		c.2653C>A	p.Arg885Ser	missense	Exon 19 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Other

Revision:

View on ClinVar

Computational scores

Other links and lift over

dbSNP: rs281875227; hg19: chr19-11132437;