1-26696649-TGGCGGC-TGGCGGCGGCGGC

Variant names:

• chr1-26696649-T-TGGCGGC
• rs1015322780
• NM_006015.6:c.255_260dupCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_006015.6(ARID1A):​c.255_260dupCGGCGG​(p.Gly86_Gly87dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000921 in 1,303,402 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. G87G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.67
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae)

LOC124900417 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6.
• BP6: Variant 1-26696649-T-TGGCGGC is Benign according to our data. Variant chr1-26696649-T-TGGCGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434330.
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006015.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	NM_006015.6	MANE Select	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	Exon 1 of 20	NP_624361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000320485.7
	ARID1A	ENST00000850904.1		c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000520984.1
	ARID1A	ENST00000457599.7	TSL:5	c.255_260dupCGGCGG	p.Gly86_Gly87dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000387636.2

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 17 AN: 146546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00380

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000676

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000890 AC: 103 AN: 1156856 Hom.: 0 Cov.: 35 AF XY: 0.0000873 AC XY: 49 AN XY: 561124

African (AFR) AF: 0.00 AC: 0 AN: 23278

American (AMR) AF: 0.00 AC: 0 AN: 9018

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 53 AN: 15180

East Asian (EAS) AF: 0.00 AC: 0 AN: 26944

South Asian (SAS) AF: 0.000182 AC: 7 AN: 38540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3116

European-Non Finnish (NFE) AF: 0.0000352 AC: 34 AN: 964918

Other (OTH) AF: 0.000194 AC: 9 AN: 46322

GnomAD4 genome AF: 0.000116 AC: 17 AN: 146546 Hom.: 0 Cov.: 32 AF XY: 0.000168 AC XY: 12 AN XY: 71476

African (AFR) AF: 0.00 AC: 0 AN: 39480

American (AMR) AF: 0.0000672 AC: 1 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.00380 AC: 13 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 4760

South Asian (SAS) AF: 0.000676 AC: 3 AN: 4440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66458

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000159

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ARID1A-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1015322780; hg19: chr1-27023140;