rs374841430
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_001130823.3(DNMT1):c.2268T>C(p.Thr756=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,844 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
DNMT1
NM_001130823.3 splice_region, synonymous
NM_001130823.3 splice_region, synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.207
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
Variant 19-10149966-A-G is Benign according to our data. Variant chr19-10149966-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 539617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.207 with no splicing effect.
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNMT1 | NM_001130823.3 | c.2268T>C | p.Thr756= | splice_region_variant, synonymous_variant | 25/41 | ENST00000359526.9 | |
DNMT1 | NM_001318730.2 | c.2220T>C | p.Thr740= | splice_region_variant, synonymous_variant | 24/40 | ||
DNMT1 | NM_001379.4 | c.2220T>C | p.Thr740= | splice_region_variant, synonymous_variant | 24/40 | ||
DNMT1 | NM_001318731.2 | c.1905T>C | p.Thr635= | splice_region_variant, synonymous_variant | 25/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNMT1 | ENST00000359526.9 | c.2268T>C | p.Thr756= | splice_region_variant, synonymous_variant | 25/41 | 1 | NM_001130823.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251484Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135912
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461660Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727168
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74344
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 11, 2018 | The p.Thr756Thr variant (rs374841430) does not alter the amino acid sequence of the DNMT1 protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in association with hearing loss in medical literature or in gene specific variation databases. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the East Asian population (identified on 4 out of18, 870 chromosomes). Based on these observations, the p.Thr756Thr variant is likely to be benign. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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