rs199832007
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_001130823.3(DNMT1):c.2667C>T(p.Tyr889=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
DNMT1
NM_001130823.3 synonymous
NM_001130823.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.97
Genes affected
DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 19-10148937-G-A is Benign according to our data. Variant chr19-10148937-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539613.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr19-10148937-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.97 with no splicing effect.
BS2
?
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.2667C>T | p.Tyr889= | synonymous_variant | 27/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.2619C>T | p.Tyr873= | synonymous_variant | 26/40 | ||
DNMT1 | NM_001379.4 | c.2619C>T | p.Tyr873= | synonymous_variant | 26/40 | ||
DNMT1 | NM_001318731.2 | c.2304C>T | p.Tyr768= | synonymous_variant | 27/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.2667C>T | p.Tyr889= | synonymous_variant | 27/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152196Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000954 AC: 24AN: 251492Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135922
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GnomAD4 exome AF: 0.000117 AC: 171AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82AN XY: 727244
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152196Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 15, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2019 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at