1-26696649-TGGCGGC-TGGCGGCGGCGGC

Position:

• chr1-26696649-TGGCGGC-TGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_006015.6(ARID1A):​c.255_260dupCGGCGG​(p.Gly86_Gly87dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000921 in 1,303,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G87G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 1.67

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_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	1/20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	1/20	1	NM_006015.6	ENSP00000320485.7
ARID1A	ENST00000457599.6	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	1/20	5		ENSP00000387636.2
ARID1A	ENST00000430799.7	c.-13+3041_-13+3046dupCGGCGG		intron_variant		5		ENSP00000390317.3
ARID1A	ENST00000637465.1	c.-13+558_-13+563dupCGGCGG		intron_variant		5		ENSP00000490650.1

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 17 AN: 146546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00380

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000676

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000890 AC: 103 AN: 1156856 Hom.: 0 Cov.: 35 AF XY: 0.0000873 AC XY: 49 AN XY: 561124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000182

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.000194

GnomAD4 genome AF: 0.000116 AC: 17 AN: 146546 Hom.: 0 Cov.: 32 AF XY: 0.000168 AC XY: 12 AN XY: 71476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.00380

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000676

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000159

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 21, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This variant, c.255_260dup, results in the insertion of 2 amino acid(s) of the ARID1A protein (p.Gly86_Gly87dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.3%). This variant has not been reported in the literature in individuals affected with ARID1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 434330). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

ARID1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1015322780; hg19: chr1-27023140;