rs876657378

Positions:

• chr19-10996249-CAGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The ENST00000344626.10(SMARCA4):​c.1636_1638del​(p.Lys546del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q544Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 ENST00000344626.10 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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, 8 uncertain in ENST00000344626.10
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000344626.10. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-10996249-CAGA-C is Pathogenic according to our data. Variant chr19-10996249-CAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 30342.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-10996249-CAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1636_1638del	p.Lys546del	inframe_deletion	10/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1636_1638del	p.Lys546del	inframe_deletion	10/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000344626.10	c.1636_1638del	p.Lys546del	inframe_deletion	10/35	1	NM_003072.5	ENSP00000343896	P4
SMARCA4	ENST00000646693.2	c.1636_1638del	p.Lys546del	inframe_deletion	10/36		NM_001387283.1	ENSP00000495368

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 18, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2022

Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 25168959, 23815551, 23010866, 24700502, 24090879, 23637025, 22426308) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657378; hg19: chr19-11106925;