rs1131692263

Positions:

• chr6-157174076-GGCAAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001374828.1(ARID1B):​c.3306_3310del​(p.Lys1103ArgfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1B NM_001374828.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.14

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-157174076-GGCAAA-G is Pathogenic according to our data. Variant chr6-157174076-GGCAAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430942.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1B	NM_001374828.1	c.3306_3310del	p.Lys1103ArgfsTer13	frameshift_variant	10/20	ENST00000636930.2	NP_001361757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1B	ENST00000636930.2	c.3306_3310del	p.Lys1103ArgfsTer13	frameshift_variant	10/20	2	NM_001374828.1	ENSP00000490491	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Jul 25, 2017

The ARID1B gene is one of 5 genes known to cause Coffis-Siris Syndrome 1 when mutated. The c.3096_3100delCAAAG (p.Lys1033ArgfsTer32) is a novel frameshift alteration leading to a premature termination codon. This deletion was not found in the 1000 Genomes, Exome Variant Server (EVS) or ExAC databases. Thus, it is presumed to be rare. The Lys1033 amino acid residue is highly conserved. Although this particular variant has not been reported in the literature, pathogenic similar alteration are reported (Hoyer et al. 2012). Based on the combined evidence, this variant is classified as likely pathogenic for Coffin-Siris Syndrome 1. -

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: rs1131692263; hg19: chr6-157495210;