chr1-26696421-CCCCGCCGCCGCCAGCAGCCTGGGCAA-C

Position:

chr1-26696421-CCCCGCCGCCGCCAGCAGCCTGGGCAA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_006015.6(ARID1A):c.31_56del(p.Ser11AlafsTer91) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,139,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARID1A
NM_006015.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.69

Variant links:

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 links:

LOC124900417 (HGNC:):

LOC124900417 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-26696421-CCCCGCCGCCGCCAGCAGCCTGGGCAA-C is Pathogenic according to our data. Variant chr1-26696421-CCCCGCCGCCGCCAGCAGCCTGGGCAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 30292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-26696421-CCCCGCCGCCGCCAGCAGCCTGGGCAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARID1A	NM_006015.6 linkuse as main transcript	c.31_56del	p.Ser11AlafsTer91	frameshift_variant	1/20	ENST00000324856.13	NP_006006.3
ARID1A	NM_139135.4 linkuse as main transcript	c.31_56del	p.Ser11AlafsTer91	frameshift_variant	1/20		NP_624361.1
LOC124900417	XM_047439473.1 linkuse as main transcript			upstream_gene_variant			XP_047295429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1A	ENST00000324856.13 linkuse as main transcript	c.31_56del	p.Ser11AlafsTer91	frameshift_variant	1/20	1	NM_006015.6	ENSP00000320485		O14497-1
ARID1A	ENST00000457599.6 linkuse as main transcript	c.31_56del	p.Ser11AlafsTer91	frameshift_variant	1/20	5		ENSP00000387636		O14497-2
ARID1A	ENST00000430799.7 linkuse as main transcript	c.-13+2817_-13+2842del		intron_variant		5		ENSP00000390317	A2
ARID1A	ENST00000637465.1 linkuse as main transcript	c.-13+334_-13+359del		intron_variant		5		ENSP00000490650

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148154

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000263

AC:

AN:

1139696

Hom.:

AF XY:

0.00000542

AC XY:

AN XY:

553350

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000638

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000258

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000105

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

148250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72448

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 14

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 18, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 19, 2024	PVS1, PS4_Moderate, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2015	- -

Coffin-Siris syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2023

The ARID1A c.31_56del (p.Ser11AlafsTer91) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in one individual with Coffin-Siris syndrome, in whom parental samples were unavailable to confirm the de novo status of the variant (PMID: 22426308; 25168959). The p.Ser11AlafsTer91 variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a de novo state. Based on the available evidence, the c.31_56del (p.Ser11AlafsTer91) variant is classified as pathogenic for Coffin-Siris syndrome. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2022

Identified in a patient with Coffin-Siris syndrome in the published literature (Tsurusaki et al., 2012; Kosho et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25168959, 24090879, 27082517, 22426308) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over