1-26696516-AGGCGGCGGCGGC-AGGCGGCGGCGGCGGCGGC

Variant names:

• chr1-26696516-A-AGGCGGC
• rs587779737
• NM_006015.6:c.123_128dupGGCGGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_006015.6(ARID1A):​c.123_128dupGGCGGC​(p.Ala42_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 0.0000784 in 1,224,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.712
• Publications: 5 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: ClinGen, Orphanet
• intellectual disability, autosomal dominant 14

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

LOC124900417 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6.
• BP6: Variant 1-26696516-A-AGGCGGC is Benign according to our data. Variant chr1-26696516-A-AGGCGGC is described in ClinVar as Likely_benign. ClinVar VariationId is 1346038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	NM_006015.6	MANE Select	c.123_128dupGGCGGC	p.Ala42_Ala43dup	disruptive_inframe_insertion	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.123_128dupGGCGGC	p.Ala42_Ala43dup	disruptive_inframe_insertion	Exon 1 of 20	NP_624361.1	O14497-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.123_128dupGGCGGC	p.Ala42_Ala43dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.123_128dupGGCGGC	p.Ala42_Ala43dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.123_128dupGGCGGC	p.Ala42_Ala43dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes AF: 0.0000671 AC: 10 AN: 149104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

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: 0.000119

Gnomad OTH AF: 0.000488

GnomAD4 exome AF: 0.0000800 AC: 86 AN: 1075484 Hom.: 0 Cov.: 35 AF XY: 0.0000999 AC XY: 51 AN XY: 510436

African (AFR) AF: 0.0000450 AC: 1 AN: 22238

American (AMR) AF: 0.00 AC: 0 AN: 7890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13582

East Asian (EAS) AF: 0.0000395 AC: 1 AN: 25310

South Asian (SAS) AF: 0.00 AC: 0 AN: 21164

European-Finnish (FIN) AF: 0.0000472 AC: 1 AN: 21170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2858

European-Non Finnish (NFE) AF: 0.0000871 AC: 80 AN: 918526

Other (OTH) AF: 0.0000702 AC: 3 AN: 42746

GnomAD4 genome AF: 0.0000671 AC: 10 AN: 149104 Hom.: 0 Cov.: 31 AF XY: 0.0000687 AC XY: 5 AN XY: 72786

African (AFR) AF: 0.00 AC: 0 AN: 40586

American (AMR) AF: 0.0000664 AC: 1 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.00 AC: 0 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67068

Other (OTH) AF: 0.000488 AC: 1 AN: 2048

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=68/32	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587779737; hg19: chr1-27023007;