1-26696649-TGGCGGC-TGGCGGCGGC

Position:

• chr1-26696649-TGGCGGC-TGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_006015.6(ARID1A):​c.258_260dup​(p.Gly86dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,303,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: ARID1A NM_006015.6 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.67

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 -4 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 1-26696649-T-TGGC is Benign according to our data. Variant chr1-26696649-T-TGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2174252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1A	NM_006015.6	c.258_260dup	p.Gly86dup	inframe_insertion	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4	c.258_260dup	p.Gly86dup	inframe_insertion	1/20		NP_624361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13	c.258_260dup	p.Gly86dup	inframe_insertion	1/20	1	NM_006015.6	ENSP00000320485
ARID1A	ENST00000457599.6	c.258_260dup	p.Gly86dup	inframe_insertion	1/20	5		ENSP00000387636
ARID1A	ENST00000430799.7	c.-13+3044_-13+3046dup		intron_variant		5		ENSP00000390317	A2
ARID1A	ENST00000637465.1	c.-13+561_-13+563dup		intron_variant		5		ENSP00000490650

Frequencies

GnomAD3 genomes AF: 0.0000955 AC: 14 AN: 146546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

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: 0.000166

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 65 AN: 1156858 Hom.: 0 Cov.: 35 AF XY: 0.0000784 AC XY: 44 AN XY: 561126

Gnomad4 AFR exome AF: 0.0000430

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000371

Gnomad4 SAS exome AF: 0.0000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000601

Gnomad4 OTH exome AF: 0.0000864

GnomAD4 genome AF: 0.0000955 AC: 14 AN: 146546 Hom.: 0 Cov.: 32 AF XY: 0.0000839 AC XY: 6 AN XY: 71476

Gnomad4 AFR AF: 0.0000507

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000166

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 05, 2023

Variant summary: ARID1A c.258_260dupCGG (p.Gly87dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 5474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.258_260dupCGG in individuals affected with Mental Retardation, Autosomal Dominant 14 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

- -

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: rs1015322780; hg19: chr1-27023140;