rs875989848

chr1-26697510-CG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_006015.6(ARID1A):c.1113del(p.Gln372SerfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,252,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ARID1A NM_006015.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.13

Genes affected

ARID1A (HGNC:11110): (AT-rich interaction domain 1A) This gene encodes a member of the SWI/SNF family, whose members 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. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-26697510-CG-C is Pathogenic according to our data. Variant chr1-26697510-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 225843.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-26697510-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.1113del	p.Gln372SerfsTer19	frameshift_variant	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.1113del	p.Gln372SerfsTer19	frameshift_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.1113del	p.Gln372SerfsTer19	frameshift_variant	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.1113del	p.Gln372SerfsTer19	frameshift_variant	1/20	5
ARID1A	ENST00000430799.7	c.-13+3899del		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+1416del		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000136 AC: 17 AN: 1252568 Hom.: 0 Cov.: 35 AF XY: 0.0000195 AC XY: 12 AN XY: 615448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000198

Gnomad4 ASJ exome AF: 0.0000501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000495

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000981

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 14 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989848; hg19: chr1-27024001;