1-26773690-CGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Position:

• chr1-26773690-CGCAGCAGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006015.6(ARID1A):​c.3999_4001dupGCA​(p.Gln1334dup) variant causes a disruptive inframe insertion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,326 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (21 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.65

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-26773690-C-CGCA is Benign according to our data. Variant chr1-26773690-C-CGCA is described in ClinVar as [Likely_benign]. Clinvar id is 235338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00255 (387/152046) while in subpopulation SAS AF= 0.0181 (87/4816). AF 95% confidence interval is 0.015. There are 4 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.3999_4001dupGCA	p.Gln1334dup	disruptive_inframe_insertion, splice_region_variant	16/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.3999_4001dupGCA	p.Gln1334dup	disruptive_inframe_insertion, splice_region_variant	16/20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.3999_4001dupGCA	p.Gln1334dup	disruptive_inframe_insertion, splice_region_variant	16/20	1	NM_006015.6	ENSP00000320485.7

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 151930 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00400 AC: 975 AN: 243834 Hom.: 7 AF XY: 0.00494 AC XY: 652 AN XY: 131940

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00366

Gnomad SAS exome AF: 0.0193

Gnomad FIN exome AF: 0.000384

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00277 AC: 4046 AN: 1461280 Hom.: 21 Cov.: 32 AF XY: 0.00325 AC XY: 2363 AN XY: 726918

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.00255 AC: 387 AN: 152046 Hom.: 4 Cov.: 32 AF XY: 0.00280 AC XY: 208 AN XY: 74336

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.0181

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00285

Bravo AF: 0.00230

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ARID1A: BS1, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 05, 2022	- -

Intellectual disability, autosomal dominant 14 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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: rs374564889; hg19: chr1-27100181;