NM_006015.6:c.1113delG

Variant names:

• chr1-26697510-CG-C
• rs875989848
• NM_006015.6:c.1113delG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_006015.6(ARID1A):​c.1113delG​(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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G371G) has been classified as Uncertain significance. 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 O:1
• Conservation: PhyloP100: 1.13
• Publications: 11 publications found

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]

ARID1A Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• intellectual disability, autosomal dominant 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 225843.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006015.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	NM_006015.6	MANE Select	c.1113delG	p.Gln372SerfsTer19	frameshift	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.1113delG	p.Gln372SerfsTer19	frameshift	Exon 1 of 20	NP_624361.1	O14497-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.1113delG	p.Gln372SerfsTer19	frameshift	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.1113delG	p.Gln372SerfsTer19	frameshift	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.1113delG	p.Gln372SerfsTer19	frameshift	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000266 AC: 9 AN: 33852 AF XY: 0.000288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.00

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

⚠️ 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: 24630

American (AMR) AF: 0.000198 AC: 3 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.0000501 AC: 1 AN: 19958

East Asian (EAS) AF: 0.00 AC: 0 AN: 27716

South Asian (SAS) AF: 0.0000495 AC: 3 AN: 60622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3580

European-Non Finnish (NFE) AF: 0.00000981 AC: 10 AN: 1018866

Other (OTH) AF: 0.00 AC: 0 AN: 51660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 14 (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs875989848; hg19: chr1-27024001; COSMIC: COSV61370581; COSMIC: COSV61370581;