rs61750052

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001130823.3(DNMT1):​c.1944C>T​(p.Phe648Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,236 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0042 ( 38 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.07
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 19-10154368-G-A is Benign according to our data. Variant chr19-10154368-G-A is described in ClinVar as [Benign]. Clinvar id is 327907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10154368-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=3.07 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00415 (6072/1461894) while in subpopulation SAS AF= 0.0172 (1481/86258). AF 95% confidence interval is 0.0164. There are 38 homozygotes in gnomad4_exome. There are 3283 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 436 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNMT1NM_001130823.3 linkuse as main transcriptc.1944C>T p.Phe648Phe synonymous_variant 22/41 ENST00000359526.9 NP_001124295.1 P26358-2I6L9H2
DNMT1NM_001318730.2 linkuse as main transcriptc.1896C>T p.Phe632Phe synonymous_variant 21/40 NP_001305659.1 P26358Q59FP7I6L9H2
DNMT1NM_001379.4 linkuse as main transcriptc.1896C>T p.Phe632Phe synonymous_variant 21/40 NP_001370.1 P26358-1I6L9H2
DNMT1NM_001318731.2 linkuse as main transcriptc.1581C>T p.Phe527Phe synonymous_variant 22/41 NP_001305660.1 P26358I6L9H2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMT1ENST00000359526.9 linkuse as main transcriptc.1944C>T p.Phe648Phe synonymous_variant 22/411 NM_001130823.3 ENSP00000352516.3 P26358-2

Frequencies

GnomAD3 genomes
AF:
0.00286
AC:
436
AN:
152224
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000916
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0149
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00359
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00456
AC:
1146
AN:
251482
Hom.:
12
AF XY:
0.00517
AC XY:
703
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.000925
Gnomad ASJ exome
AF:
0.00258
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0182
Gnomad FIN exome
AF:
0.00134
Gnomad NFE exome
AF:
0.00408
Gnomad OTH exome
AF:
0.00342
GnomAD4 exome
AF:
0.00415
AC:
6072
AN:
1461894
Hom.:
38
Cov.:
31
AF XY:
0.00451
AC XY:
3283
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000747
Gnomad4 AMR exome
AF:
0.000961
Gnomad4 ASJ exome
AF:
0.00283
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0172
Gnomad4 FIN exome
AF:
0.00168
Gnomad4 NFE exome
AF:
0.00367
Gnomad4 OTH exome
AF:
0.00430
GnomAD4 genome
AF:
0.00286
AC:
436
AN:
152342
Hom.:
4
Cov.:
32
AF XY:
0.00298
AC XY:
222
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000914
Gnomad4 AMR
AF:
0.00346
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0149
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00359
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.00326
Hom.:
1
Bravo
AF:
0.00259
Asia WGS
AF:
0.00520
AC:
18
AN:
3478
EpiCase
AF:
0.00333
EpiControl
AF:
0.00367

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 01, 2016This 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. -
Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 31, 2022- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
14
DANN
Benign
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61750052; hg19: chr19-10265044; API