rs797045277

chr6-157198907-G-Achr6-157198907-G-Cchr6-157198907-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001374828.1(ARID1B):c.4479G>A(p.Pro1493=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1493P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID1B NM_001374828.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 9.43

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.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 6-157198907-G-A is Pathogenic according to our data. Variant chr6-157198907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-157198907-G-A is described in Lovd as [Pathogenic]. Variant chr6-157198907-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID1B	NM_001374828.1	c.4479G>A	p.Pro1493=	splice_region_variant, synonymous_variant	17/20	ENST00000636930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID1B	ENST00000636930.2	c.4479G>A	p.Pro1493=	splice_region_variant, synonymous_variant	17/20	2	NM_001374828.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1445994 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. [PMID 22405089, 27474218, 29286531, 28323383] -
Likely 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	Jan 12, 2017	- -

See cases Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 10, 2021	ACMG categories: PS5,PM2,PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	Apr 26, 2021	PVS1_strong;PM2_supporting;PM6_moderate -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2022	This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome and/or Coffin-Siris syndrome (PMID: 22405089, 27474218, 28323383). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1370 of the ARID1B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ARID1B protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 210291). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17 and introduces a premature termination codon (PMID: 22405089). The resulting mRNA is expected to undergo nonsense-mediated decay. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2022	Affects the splice donor site and induces skipping of exon 17 causing a frameshift leading to a premature Stop codon (p.Arg1338ArgfsX76) (Hoyer et al., 2012); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30349098, 22405089, 28323383, 27474218, 29286531, 15057123, 31406558) -

ARID1B-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2023

The ARID1B c.4110G>A variant is not predicted to result in an amino acid change (p.=). This variant is predicted to weaken the canonical splice donor site (Alamut Visual Plus v1.6.1). This variant has been reported in multiple individuals with Coffin-Siris syndrome and the majority of cases were found to be de novo (see for example, Hoyer et al. 2012. PubMed ID: 22405089; Mignot et al. 2016. PubMed ID: 27474218; Tumienė et al. 2018. PubMed ID: 29286531; van der Sluijs et al. 2019. PubMed ID: 30349098). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. cDNA analyses indicated that this variant causes skipping of exon 17 and a shift to the translation reading frame (p.Arg1338Argfs*76, Hoyer et al. 2012. PubMed ID: 22405089) This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.4110G>A (p.P1370P) alteration is located in coding exon 17 of the ARID1B gene. This nucleotide substitution does not change the proline (P) at codon 1370. However, this change occurs in the last base pair of coding exon 17, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as a de novo occurrence in multiple unrelated individuals with CSS (Hoyer, 2012; Mignot, 2016; Zweier, 2017). This nucleotide position is highly conserved in available vertebrate species. RNA functional analysis demonstrated that the alteration leads to out-of-frame skipping of exon 17 (Hoyer, 2012). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic. -

ARID1B-related BAFopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

Constipation;C0036572:Seizure;C0349588:Short stature;C2315100:Failure to thrive;C3806482:Recurrent respiratory infections;C4551563:Microcephaly;C5574742:Decreased body weight Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.070		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: rs797045277; hg19: chr6-157520041;