1-26696885-TCGCCGCCGC-TCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_006015.6(ARID1A):c.492_494dup(p.Ala166dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,348,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V161V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: ARID1A NM_006015.6 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.849

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 Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-26696885-T-TCGC is Benign according to our data. Variant chr1-26696885-T-TCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434333.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000763 (917/1202620) while in subpopulation NFE AF= 0.000877 (864/985420). AF 95% confidence interval is 0.000828. There are 0 homozygotes in gnomad4_exome. There are 402 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.492_494dup	p.Ala166dup	inframe_insertion	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.492_494dup	p.Ala166dup	inframe_insertion	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.492_494dup	p.Ala166dup	inframe_insertion	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.492_494dup	p.Ala166dup	inframe_insertion	1/20	5
ARID1A	ENST00000430799.7	c.-13+3278_-13+3280dup		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+795_-13+797dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 62 AN: 145868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000710

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000839 AC: 2 AN: 23828 Hom.: 0 AF XY: 0.0000758 AC XY: 1 AN XY: 13200

Gnomad AFR exome AF: 0.00

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: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000763 AC: 917 AN: 1202620 Hom.: 0 Cov.: 35 AF XY: 0.000689 AC XY: 402 AN XY: 583278

Gnomad4 AFR exome AF: 0.000293

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000877

Gnomad4 OTH exome AF: 0.000953

GnomAD4 genome AF: 0.000425 AC: 62 AN: 146000 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 23 AN XY: 71308

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000710

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000355

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 22, 2015

- -

ARID1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2023

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: rs759913677; hg19: chr1-27023376;