chr1-26696448-CCCG-C

Variant names:

• chr1-26696448-CCCG-C
• rs748085214
• NM_006015.6:c.60_62delGCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_006015.6(ARID1A):​c.60_62delGCC​(p.Pro21del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,268,634 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P20P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.288
• Publications: 2 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006015.6
• BP6: Variant 1-26696448-CCCG-C is Benign according to our data. Variant chr1-26696448-CCCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 770843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.60_62delGCC	p.Pro21del	disruptive_inframe_deletion	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.60_62delGCC	p.Pro21del	disruptive_inframe_deletion	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.60_62delGCC	p.Pro21del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000320485.7	O14497-1
	ARID1A	ENST00000850904.1		c.60_62delGCC	p.Pro21del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000520984.1	A0ABJ7H312
	ARID1A	ENST00000457599.7	TSL:5	c.60_62delGCC	p.Pro21del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000387636.2	O14497-2

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 147006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0121 AC: 185 AN: 15288 AF XY: 0.0123

Gnomad AFR exome AF: 0.00847

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00575

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00131 AC: 1468 AN: 1121628 Hom.: 0 AF XY: 0.00172 AC XY: 933 AN XY: 543258

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00105 AC: 24 AN: 22820

American (AMR) AF: 0.00489 AC: 55 AN: 11238

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 45 AN: 15490

East Asian (EAS) AF: 0.00135 AC: 34 AN: 25134

South Asian (SAS) AF: 0.00878 AC: 323 AN: 36800

European-Finnish (FIN) AF: 0.00243 AC: 56 AN: 23050

Middle Eastern (MID) AF: 0.00166 AC: 5 AN: 3018

European-Non Finnish (NFE) AF: 0.000907 AC: 852 AN: 939796

Other (OTH) AF: 0.00167 AC: 74 AN: 44282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 147006 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 1 AN XY: 71860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000249 AC: 1 AN: 40128

American (AMR) AF: 0.0000670 AC: 1 AN: 14924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 4988

South Asian (SAS) AF: 0.00 AC: 0 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66086

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00313 AC: 10 AN: 3214

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ARID1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs748085214; hg19: chr1-27022939; COSMIC: COSV61387765; COSMIC: COSV61387765;