1-26696885-TCGCCGCCGC-TCGC

Position:

• chr1-26696885-TCGCCGCCGC-TCGC

Variant summary

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

The NM_006015.6(ARID1A):​c.489_494delCGCCGC​(p.Ala164_Ala165del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,348,618 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. A163A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.489_494delCGCCGC	p.Ala164_Ala165del	disruptive_inframe_deletion	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.489_494delCGCCGC	p.Ala164_Ala165del	disruptive_inframe_deletion	1/20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.489_494delCGCCGC	p.Ala164_Ala165del	disruptive_inframe_deletion	1/20	1	NM_006015.6	ENSP00000320485.7
ARID1A	ENST00000457599.6	c.489_494delCGCCGC	p.Ala164_Ala165del	disruptive_inframe_deletion	1/20	5		ENSP00000387636.2
ARID1A	ENST00000430799.7	c.-13+3275_-13+3280delCGCCGC		intron_variant		5		ENSP00000390317.3
ARID1A	ENST00000637465.1	c.-13+792_-13+797delCGCCGC		intron_variant		5		ENSP00000490650.1

Frequencies

GnomAD3 genomes AF: 0.0000411 AC: 6 AN: 145868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000223

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000420 AC: 1 AN: 23828 Hom.: 0 AF XY: 0.0000758 AC XY: 1 AN XY: 13200

Gnomad AFR exome AF: 0.000954

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000524 AC: 63 AN: 1202618 Hom.: 0 AF XY: 0.0000600 AC XY: 35 AN XY: 583276

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.000105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000729

Gnomad4 SAS exome AF: 0.0000211

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000548

Gnomad4 OTH exome AF: 0.0000414

GnomAD4 genome AF: 0.0000411 AC: 6 AN: 146000 Hom.: 0 Cov.: 32 AF XY: 0.0000421 AC XY: 3 AN XY: 71308

Gnomad4 AFR AF: 0.0000762

Gnomad4 AMR AF: 0.0000671

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000223

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000151

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This variant, c.489_494del, results in the deletion of 2 amino acid(s) of the ARID1A protein (p.Ala166_Ala167del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759913677, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ARID1A-related conditions. 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. -

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: rs759913677; hg19: chr1-27023376;