rs1020363356
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_001130823.3(DNMT1):āc.526A>Cā(p.Lys176Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K176R) has been classified as Likely benign.
Frequency
Consequence
NM_001130823.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.526A>C | p.Lys176Gln | missense_variant | 6/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.478A>C | p.Lys160Gln | missense_variant | 5/40 | ||
DNMT1 | NM_001379.4 | c.478A>C | p.Lys160Gln | missense_variant | 5/40 | ||
DNMT1 | NM_001318731.2 | c.163A>C | p.Lys55Gln | missense_variant | 6/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.526A>C | p.Lys176Gln | missense_variant | 6/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152004Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74262
ClinVar
Submissions by phenotype
Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2022 | This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the DNMT1 protein (p.Lys176Gln). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 573940). - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at