1-26696448-C-CCCGCCG

Position:

• chr1-26696448-C-CCCGCCG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_006015.6(ARID1A):​c.57_62dup​(p.Pro20_Pro21dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,285,864 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: ARID1A NM_006015.6 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 0.242

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]

LOC124900417 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 1-26696448-C-CCCGCCG is Benign according to our data. Variant chr1-26696448-C-CCCGCCG is described in ClinVar as [Likely_benign]. Clinvar id is 591469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.57_62dup	p.Pro20_Pro21dup	inframe_insertion	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.57_62dup	p.Pro20_Pro21dup	inframe_insertion	1/20		NP_624361.1
LOC124900417	XM_047439473.1			upstream_gene_variant			XP_047295429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.57_62dup	p.Pro20_Pro21dup	inframe_insertion	1/20	1	NM_006015.6	ENSP00000320485
ARID1A	ENST00000457599.6	c.57_62dup	p.Pro20_Pro21dup	inframe_insertion	1/20	5		ENSP00000387636
ARID1A	ENST00000430799.7	c.-13+2843_-13+2848dup		intron_variant		5		ENSP00000390317	A2
ARID1A	ENST00000637465.1	c.-13+360_-13+365dup		intron_variant		5		ENSP00000490650

Frequencies

GnomAD3 genomes AF: 0.000456 AC: 67 AN: 147056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000378

Gnomad OTH AF: 0.000495

GnomAD4 exome AF: 0.000422 AC: 481 AN: 1138710 Hom.: 0 Cov.: 35 AF XY: 0.000420 AC XY: 232 AN XY: 552484

Gnomad4 AFR exome AF: 0.000303

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: 0.00365

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.000221

GnomAD4 genome AF: 0.000455 AC: 67 AN: 147154 Hom.: 1 Cov.: 32 AF XY: 0.000514 AC XY: 37 AN XY: 71992

Gnomad4 AFR AF: 0.000373

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00271

Gnomad4 NFE AF: 0.000378

Gnomad4 OTH AF: 0.000490

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	- -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 04, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ARID1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

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: rs748085214; hg19: chr1-27022939;