19-10156401-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001130823.3(DNMT1):c.1389A>G(p.Pro463Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,605,870 control chromosomes in the GnomAD database, including 205,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 19965 hom., cov: 29)

Exomes 𝑓: 0.50 ( 185874 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -8.10

Publications

115 publications found

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]

DNMT1 Gene-Disease associations (from GenCC):

autosomal dominant cerebellar ataxia, deafness and narcolepsy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

DNMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 19-10156401-T-C is Benign according to our data. Variant chr19-10156401-T-C is described in ClinVar as Benign. ClinVar VariationId is 257536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNMT1	NM_001130823.3 link	c.1389A>G	p.Pro463Pro	synonymous_variant	Exon 18 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 link	c.1341A>G	p.Pro447Pro	synonymous_variant	Exon 17 of 40		NP_001305659.1
DNMT1	NM_001379.4 link	c.1341A>G	p.Pro447Pro	synonymous_variant	Exon 17 of 40		NP_001370.1
DNMT1	NM_001318731.2 link	c.1026A>G	p.Pro342Pro	synonymous_variant	Exon 18 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.1389A>G	p.Pro463Pro	synonymous_variant	Exon 18 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes

AF:

0.510

AC:

77266

AN:

151414

Hom.:

19932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.508

Gnomad AMI

AF:

0.559

Gnomad AMR

AF:

0.493

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.487

GnomAD2 exomes

AF:

0.519

AC:

130376

AN:

251354

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.512

Gnomad AMR exome

AF:

0.484

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.521

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.513

GnomAD4 exome

AF:

0.504

AC:

732721

AN:

1454336

Hom.:

185874

Cov.:

AF XY:

0.505

AC XY:

365549

AN XY:

723916

show subpopulations

African (AFR)

AF:

0.510

AC:

16964

AN:

33280

American (AMR)

AF:

0.482

AC:

21517

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14417

AN:

26010

East Asian (EAS)

AF:

0.622

AC:

24593

AN:

39538

South Asian (SAS)

AF:

0.537

AC:

46259

AN:

86116

European-Finnish (FIN)

AF:

0.524

AC:

27766

AN:

53010

Middle Eastern (MID)

AF:

0.562

AC:

3222

AN:

5736

European-Non Finnish (NFE)

AF:

0.495

AC:

547238

AN:

1106008

Other (OTH)

AF:

0.512

AC:

30745

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

16724

33448

50172

66896

83620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16124

32248

48372

64496

80620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.511

AC:

77363

AN:

151534

Hom.:

19965

Cov.:

AF XY:

0.512

AC XY:

37910

AN XY:

74036

show subpopulations

African (AFR)

AF:

0.509

AC:

21025

AN:

41316

American (AMR)

AF:

0.493

AC:

7492

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

1927

AN:

3468

East Asian (EAS)

AF:

0.675

AC:

3453

AN:

5118

South Asian (SAS)

AF:

0.547

AC:

2614

AN:

4782

European-Finnish (FIN)

AF:

0.515

AC:

5393

AN:

10462

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.497

AC:

33763

AN:

67896

Other (OTH)

AF:

0.491

AC:

1031

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1870

3740

5610

7480

9350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.500

Hom.:

84013

Bravo

AF:

0.505

Asia WGS

AF:

0.603

AC:

2096

AN:

3478

EpiCase

AF:

0.491

EpiControl

AF:

0.487

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal dominant cerebellar ataxia, deafness and narcolepsy

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.31

(source)

DANN

Benign

0.36

PhyloP100

-8.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over