rs886041706

chr6-157206703-TAGAA-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001374828.1(ARID1B):c.5939_5942del(p.Lys1980SerfsTer17) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1B NM_001374828.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.09

Genes affected

ARID1B (HGNC:18040): (AT-rich interaction domain 1B) This locus encodes an AT-rich DNA interacting domain-containing protein. The encoded protein is a component of the SWI/SNF chromatin remodeling complex and may play a role in cell-cycle activation. The protein encoded by this locus is similar to AT-rich interactive domain-containing protein 1A. These two proteins function as alternative, mutually exclusive ARID-subunits of the SWI/SNF complex. The associated complexes play opposing roles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 75 pathogenic variants in the truncated region.
• PP5: Variant 6-157206703-TAGAA-T is Pathogenic according to our data. Variant chr6-157206703-TAGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 280515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-157206703-TAGAA-T is described in Lovd as [Likely_pathogenic]. Variant chr6-157206703-TAGAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.5939_5942del	p.Lys1980SerfsTer17	frameshift_variant	20/20	ENST00000636930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.5939_5942del	p.Lys1980SerfsTer17	frameshift_variant	20/20	2	NM_001374828.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 15, 2020	ACMG codes:PVS1, PS2, PS4M, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 20 of 20). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many downstream variants predicted to cause a truncated protein have been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients as pathogenic (ClinVar, PMID: 28323383). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 29, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2016	The c.5570_5573delAAGA pathogenic variant in the ARID1B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Lysine 1857, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Lys1857SerfsX17. This variant is predicted to cause loss of normal protein function through protein truncation. The c.5570_5573delAAGA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.5570_5573delAAGA as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2023	This sequence change creates a premature translational stop signal (p.Lys1857Serfs*17) in the ARID1B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 393 amino acid(s) of the ARID1B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 28323383, 28454995). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280515). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2018

- -

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: rs886041706; hg19: chr6-157527837;