chr19-10139794-C-T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2
The NM_001130823.3(DNMT1):c.3830G>A(p.Arg1277Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,592,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1277R) has been classified as Likely benign.
Frequency
Consequence
NM_001130823.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant cerebellar ataxia, deafness and narcolepsyInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
- hereditary sensory neuropathy-deafness-dementia syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.3830G>A | p.Arg1277Gln | missense_variant | Exon 34 of 41 | ENST00000359526.9 | NP_001124295.1 | |
DNMT1 | NM_001318730.2 | c.3782G>A | p.Arg1261Gln | missense_variant | Exon 33 of 40 | NP_001305659.1 | ||
DNMT1 | NM_001379.4 | c.3782G>A | p.Arg1261Gln | missense_variant | Exon 33 of 40 | NP_001370.1 | ||
DNMT1 | NM_001318731.2 | c.3467G>A | p.Arg1156Gln | missense_variant | Exon 34 of 41 | NP_001305660.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152024Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000385 AC: 8AN: 207858 AF XY: 0.0000536 show subpopulations
GnomAD4 exome AF: 0.0000229 AC: 33AN: 1440312Hom.: 0 Cov.: 33 AF XY: 0.0000210 AC XY: 15AN XY: 714516 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152024Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74268 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The p.R1261Q variant (also known as c.3782G>A), located in coding exon 33 of the DNMT1 gene, results from a G to A substitution at nucleotide position 3782. The arginine at codon 1261 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1277 of the DNMT1 protein (p.Arg1277Gln). This variant is present in population databases (rs774073234, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at