rs1555611722
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_Very_Strong
The NM_001005273.3(CHD3):c.2953C>T(p.Arg985Trp) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R985P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001005273.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD3 | NM_001005273.3 | c.2953C>T | p.Arg985Trp | missense_variant | 18/40 | ENST00000330494.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD3 | ENST00000330494.12 | c.2953C>T | p.Arg985Trp | missense_variant | 18/40 | 1 | NM_001005273.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Snijders Blok-Campeau syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Feb 19, 2019 | This variant is interpreted as a Pathogenic for Snijders Blok-Campeau syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6-Strong :PM6 upgraded in strength to Strong due to multiple de novo occurrences (PMID:30397230). PM1-supporting : PM1 downgraded in strength to Supporting. PP2 : Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. PS4-Moderate : PS4 downgraded in strength to Moderate. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Aug 31, 2022 | PM2, PM5, PP2, PP3, PP5 - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2019 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.3130C>T (p.R1044W) alteration is located in coding exon 18 of the CHD3 gene. This alteration results from a C to T substitution at nucleotide position 3130, causing the arginine (R) at amino acid position 1044 to be replaced by a tryptophan (W). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CHD3 c.3130C>T alteration was not observed, with coverage at this position. Based on data from the NHLBI Exome Sequencing Project (ESP), the CHD3 c.3130C>T alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported once from a cohort of individuals with developmental disorders (DDD, 2017)._x000D_ _x000D_ Deciphering Developmental Disorders Study. Nature. (2017) 542(7642). PMID:28135719. Supplemental 1 The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R1044 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.R1044W amino acid is located in the SNF2-like ATPase/helicase domain, which consists of two subdomains; a helicase ATP-binding lobe and C-terminal lobe. The majority of mutations have been observed to cluster within or around this domain. This domain uses ATPase activity to provide energy for nucleosome remodeling (Snijders Blok, 2018). The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.R1044W alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | Jan 14, 2021 | - - |
Intellectual disability Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | CHU Sainte-Justine Research Center, University of Montreal | May 03, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at