rs397509392
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001130823.3(DNMT1):c.1709C>T(p.Ala570Val) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A570T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001130823.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.1709C>T | p.Ala570Val | missense_variant | 21/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.1661C>T | p.Ala554Val | missense_variant | 20/40 | ||
DNMT1 | NM_001379.4 | c.1661C>T | p.Ala554Val | missense_variant | 20/40 | ||
DNMT1 | NM_001318731.2 | c.1346C>T | p.Ala449Val | missense_variant | 21/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.1709C>T | p.Ala570Val | missense_variant | 21/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 37
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant cerebellar ataxia, deafness and narcolepsy Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 2012 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2022 | Published functional studies demonstrate a damaging effect resulting in aberrant protein localization and reduced cellular ATP levels (Mishima et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24727570, 24709307, 27602171, 27869457, 32754641, 31984424, 31680384, 25678562, 23521649, 25942534, 22328086) - |
Hereditary sensory neuropathy-deafness-dementia syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DNMT1 function (PMID: 31984424). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 50920). This missense change has been observed in individual(s) with cerebellar ataxia, deafness, and narcolepsy (PMID: 22328086). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 570 of the DNMT1 protein (p.Ala570Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at