rs75443147
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001130823.3(DNMT1):c.1500C>T(p.Ala500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,048 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0058 ( 19 hom., cov: 32)
Exomes 𝑓: 0.0039 ( 116 hom. )
Consequence
DNMT1
NM_001130823.3 synonymous
NM_001130823.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.79
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
Variant 19-10155049-G-A is Benign according to our data. Variant chr19-10155049-G-A is described in ClinVar as [Benign]. Clinvar id is 327910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10155049-G-A is described in Lovd as [Likely_benign]. Variant chr19-10155049-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-3.79 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00585 (890/152244) while in subpopulation EAS AF= 0.0342 (177/5178). AF 95% confidence interval is 0.0301. There are 19 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 890 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.1500C>T | p.Ala500= | synonymous_variant | 20/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.1452C>T | p.Ala484= | synonymous_variant | 19/40 | ||
DNMT1 | NM_001379.4 | c.1452C>T | p.Ala484= | synonymous_variant | 19/40 | ||
DNMT1 | NM_001318731.2 | c.1137C>T | p.Ala379= | synonymous_variant | 20/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.1500C>T | p.Ala500= | synonymous_variant | 20/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes ? AF: 0.00586 AC: 891AN: 152126Hom.: 19 Cov.: 32
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GnomAD3 exomes AF: 0.00874 AC: 2198AN: 251412Hom.: 41 AF XY: 0.00859 AC XY: 1167AN XY: 135878
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GnomAD4 exome AF: 0.00389 AC: 5687AN: 1461804Hom.: 116 Cov.: 36 AF XY: 0.00395 AC XY: 2872AN XY: 727206
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GnomAD4 genome ? AF: 0.00585 AC: 890AN: 152244Hom.: 19 Cov.: 32 AF XY: 0.00789 AC XY: 587AN XY: 74426
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 15, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at