rs749970078

Positions:

• chr1-26697129-CGCG-C
• chr1-26697129-CGCG-CGCGGCG

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_006015.6(ARID1A):​c.735_737del​(p.Ala247del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,437,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ARID1A NM_006015.6 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.735_737del	p.Ala247del	inframe_deletion	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.735_737del	p.Ala247del	inframe_deletion	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.735_737del	p.Ala247del	inframe_deletion	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.735_737del	p.Ala247del	inframe_deletion	1/20	5
ARID1A	ENST00000430799.7	c.-13+3521_-13+3523del		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+1038_-13+1040del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 151218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000719 AC: 4 AN: 55646 Hom.: 0 AF XY: 0.0000935 AC XY: 3 AN XY: 32094

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000817

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 110 AN: 1285982 Hom.: 0 AF XY: 0.0000809 AC XY: 51 AN XY: 630762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000323

Gnomad4 FIN exome AF: 0.0000446

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.0000190

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 151218 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73860

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ARID1A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.735_737del, results in the deletion of 1 amino acid(s) of the ARID1A protein (p.Ala247del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs749970078; hg19: chr1-27023620;