1-26696516-AGGCGGCGGCGGC-AGGCGGCGGCGGCGGC

Position:

• chr1-26696516-AGGCGGCGGCGGC-AGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_006015.6(ARID1A):​c.126_128dupGGC​(p.Ala43dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,224,682 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (22 hom., cov: 31)
  • Exomes 𝑓: 0.00081 (8 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.712

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 -15 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 1-26696516-A-AGGC is Benign according to our data. Variant chr1-26696516-A-AGGC is described in ClinVar as [Likely_benign]. Clinvar id is 126309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00813 (1213/149202) while in subpopulation AFR AF= 0.0275 (1120/40686). AF 95% confidence interval is 0.0262. There are 22 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.126_128dupGGC	p.Ala43dup	disruptive_inframe_insertion	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.126_128dupGGC	p.Ala43dup	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.126_128dupGGC	p.Ala43dup	disruptive_inframe_insertion	1/20	1	NM_006015.6	ENSP00000320485.7
ARID1A	ENST00000457599.6	c.126_128dupGGC	p.Ala43dup	disruptive_inframe_insertion	1/20	5		ENSP00000387636.2
ARID1A	ENST00000430799.7	c.-13+2912_-13+2914dupGGC		intron_variant		5		ENSP00000390317.3
ARID1A	ENST00000637465.1	c.-13+429_-13+431dupGGC		intron_variant		5		ENSP00000490650.1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1211 AN: 149098 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000407

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000313

Gnomad OTH AF: 0.00879

GnomAD4 exome AF: 0.000814 AC: 875 AN: 1075480 Hom.: 8 Cov.: 35 AF XY: 0.000756 AC XY: 386 AN XY: 510436

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000790

Gnomad4 SAS exome AF: 0.000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00813 AC: 1213 AN: 149202 Hom.: 22 Cov.: 31 AF XY: 0.00770 AC XY: 561 AN XY: 72898

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.00338

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000408

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000313

Gnomad4 OTH AF: 0.00870

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 02, 2016

- -

Intellectual disability, autosomal dominant 14 Benign:1

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: rs587779737; hg19: chr1-27023007;