NM_001374828.1:c.5239C>T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001374828.1(ARID1B):c.5239C>T(p.Arg1747*) 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001374828.1 stop_gained
Scores
Clinical Significance
Conservation
Publications
- Coffin-Siris syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina, ClinGen
- Coffin-Siris syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001374828.1. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ARID1B | NM_001374828.1 | MANE Select | c.5239C>T | p.Arg1747* | stop_gained | Exon 18 of 20 | NP_001361757.1 | ||
| ARID1B | NM_001438482.1 | c.5368C>T | p.Arg1790* | stop_gained | Exon 19 of 21 | NP_001425411.1 | |||
| ARID1B | NM_001438483.1 | c.5281C>T | p.Arg1761* | stop_gained | Exon 19 of 21 | NP_001425412.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ARID1B | ENST00000636930.2 | TSL:2 MANE Select | c.5239C>T | p.Arg1747* | stop_gained | Exon 18 of 20 | ENSP00000490491.2 | ||
| ARID1B | ENST00000346085.10 | TSL:1 | c.5119C>T | p.Arg1707* | stop_gained | Exon 19 of 21 | ENSP00000344546.5 | ||
| ARID1B | ENST00000350026.11 | TSL:1 | c.5080C>T | p.Arg1694* | stop_gained | Exon 17 of 19 | ENSP00000055163.8 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Coffin-Siris syndrome 1 Pathogenic:9
PVS1_very strong;PS4_strong;PM2_supporting
PVS1,PS2, PM2
The p.Arg1707* variant in the ARID1B gene has been previously reported in at least 4 individuals with intellectual disability and/or a phenotype consistent with Coffin-Siris syndrome (Al-Shamsi et al., 2016; Gao et al., 2018; van der Sluijs et al., 2019). Note that this variant is referred to as p.Arg1624* in the literature. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Arg1707* variant leads to a premature stop codon in exon 18 of 20 exons, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the ARID1B gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg1707* variant as pathogenic for autosomal dominant ARID1B-related disorder based on the information above. [ACMG evidence codes used: PVS1; PS2; PM2]
This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory as a de novo finding in a 4-year-old male with global delays, dysmorphic features, macrocephaly, partial agenesis of corpus callosum, PFO, hirsutism.
NM_001374828.1:c.5239C>T is a nonsense mutation in ARID1B which results in a premature stop codon at position 1747 likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with ASD, global developmental delay, macrocephaly, dysmorphic features, all core features of in the autosomal dominant condition Coffin-Siris syndrome (OMIM: 135900) (PP4). The variant has been identified as a de novo occurrence in a family without family history, but without confirmation of paternity and maternity (PM6). The variant is absent in the gnomAD population database, as would be expected for a rare genetic condition such as Coffin-Siris syndrome (PM2). In summary, this variant meets criteria to be classified as pathogenic for Coffin-Siris syndrome based on the ACMG/AMP criteria applied: PVS1, PM6, PM2, PP4
not provided Pathogenic:4
ARID1B: PVS1, PM2
This sequence change creates a premature translational stop signal (p.Arg1624*) in the ARID1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARID1B are known to be pathogenic (PMID: 25674384, 30349098). 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: 27391121; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 503753). For these reasons, this variant has been classified as Pathogenic.
Nonsense 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: 34440449, 30440138, 27391121, 30349098, 28191889)
Inborn genetic diseases Pathogenic:1
The c.4870C>T (p.R1624*) alteration, located in exon 18 (coding exon 18) of the ARID1B gene, consists of a C to T substitution at nucleotide position 4870. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 1624. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with suspected ARID1B-related Coffin-Siris syndrome (Sekiguchi, 2019; Saleh, 2021). Based on the available evidence, this alteration is classified as pathogenic.
ARID1B-related BAFopathy Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at