6-157207109-C-T

Variant summary

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

The NM_001374828.1(ARID1B):​c.6337C>T​(p.Arg2113*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ARID1B
NM_001374828.1 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.99
Variant links:
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]

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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 is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-157207109-C-T is Pathogenic according to our data. Variant chr6-157207109-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 210306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-157207109-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARID1BNM_001374828.1 linkuse as main transcriptc.6337C>T p.Arg2113* stop_gained 20/20 ENST00000636930.2 NP_001361757.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARID1BENST00000636930.2 linkuse as main transcriptc.6337C>T p.Arg2113* stop_gained 20/202 NM_001374828.1 ENSP00000490491.2 Q8NFD5-3A0A6Q8NVI4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Coffin-Siris syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityJan 29, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 31, 2014- -
ARID1B-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 13, 2024The ARID1B c.5968C>T variant is predicted to result in premature protein termination (p.Arg1990*). This variant has been reported as a recurrent variant in individuals with Coffin-Siris syndrome, and it was confirmed to have occurred de novo in at least two of the reported patients (Santen et al. 2013. PubMed ID: 23929686; Patient #8 in Figure 1, Mignot et al. 2016. PubMed ID: 27474218). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ARID1B are expected to be pathogenic. This variant is interpreted as pathogenic. -
Dysphagia;C0040485:Torticollis;C0151526:Premature birth;C0206733:Capillary hemangioma;C0349588:Short stature;C0557874:Global developmental delay;C1844820:Joint hypermobility;C1849075:Relative macrocephaly;C1858120:Generalized hypotonia;C4551629:Congenital talipes calcaneovalgus Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Personalized Medicine, Children's Hospital Los Angeles-- -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Personalized Medicine, Children's Hospital Los AngelesDec 21, 2022- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 16, 2022Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 260 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23929686, 24090879, 24866042, 27474218, 30755392) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D;D;D;D
Vest4
0.86
GERP RS
5.3

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

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

Other links and lift over

dbSNP: rs797045283; hg19: chr6-157528243; COSMIC: COSV51666367; API