1-26696448-C-CCCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_006015.6(ARID1A):c.60_62dup(p.Pro20dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,285,876 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 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: ARID1A NM_006015.6 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.242

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]

LOC124900417 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 1-26696448-C-CCCG is Benign according to our data. Variant chr1-26696448-C-CCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434329.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000537 (79/147154) while in subpopulation AFR AF= 0.00176 (71/40236). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1A	NM_006015.6	c.60_62dup	p.Pro20dup	inframe_insertion	1/20	ENST00000324856.13
ARID1A	NM_139135.4	c.60_62dup	p.Pro20dup	inframe_insertion	1/20
LOC124900417	XM_047439473.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1A	ENST00000324856.13	c.60_62dup	p.Pro20dup	inframe_insertion	1/20	1	NM_006015.6
ARID1A	ENST00000457599.6	c.60_62dup	p.Pro20dup	inframe_insertion	1/20	5
ARID1A	ENST00000430799.7	c.-13+2846_-13+2848dup		intron_variant		5		A2
ARID1A	ENST00000637465.1	c.-13+363_-13+365dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 79 AN: 147056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000121

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000659 AC: 75 AN: 1138722 Hom.: 0 Cov.: 35 AF XY: 0.0000633 AC XY: 35 AN XY: 552488

Gnomad4 AFR exome AF: 0.00151

Gnomad4 AMR exome AF: 0.0000860

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000387

Gnomad4 SAS exome AF: 0.000131

Gnomad4 FIN exome AF: 0.0000419

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.000111

GnomAD4 genome AF: 0.000537 AC: 79 AN: 147154 Hom.: 0 Cov.: 32 AF XY: 0.000583 AC XY: 42 AN XY: 71992

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000121

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000635

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	- -

Astrocytoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston

-

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ARID1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs748085214; hg19: chr1-27022939;