chr19-10154636-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.1782A>G(p.Thr594Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,614,176 control chromosomes in the GnomAD database, including 787,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 74771 hom., cov: 32)

Exomes 𝑓: 0.99 ( 713121 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.60

Publications

30 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=-0.89).

BP6

Variant 19-10154636-T-C is Benign according to our data. Variant chr19-10154636-T-C is described in ClinVar as Benign. ClinVar VariationId is 257537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNMT1	NM_001130823.3 link	c.1782A>G	p.Thr594Thr	synonymous_variant	Exon 21 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 link	c.1734A>G	p.Thr578Thr	synonymous_variant	Exon 20 of 40		NP_001305659.1
DNMT1	NM_001379.4 link	c.1734A>G	p.Thr578Thr	synonymous_variant	Exon 20 of 40		NP_001370.1
DNMT1	NM_001318731.2 link	c.1419A>G	p.Thr473Thr	synonymous_variant	Exon 21 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.1782A>G	p.Thr594Thr	synonymous_variant	Exon 21 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes

AF:

0.991

AC:

150800

AN:

152192

Hom.:

74713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.997

Gnomad AMI

AF:

0.987

Gnomad AMR

AF:

0.993

Gnomad ASJ

AF:

0.984

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

0.992

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.991

GnomAD2 exomes

AF:

0.991

AC:

248643

AN:

250956

AF XY:

0.991

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.987

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.990

Gnomad NFE exome

AF:

0.986

Gnomad OTH exome

AF:

0.988

GnomAD4 exome

AF:

0.988

AC:

1443923

AN:

1461866

Hom.:

713121

Cov.:

AF XY:

0.988

AC XY:

718589

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.998

AC:

33412

AN:

33480

American (AMR)

AF:

0.992

AC:

44346

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.986

AC:

25770

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

0.999

AC:

86152

AN:

86258

European-Finnish (FIN)

AF:

0.989

AC:

52829

AN:

53392

Middle Eastern (MID)

AF:

0.993

AC:

5727

AN:

5768

European-Non Finnish (NFE)

AF:

0.986

AC:

1096302

AN:

1112012

Other (OTH)

AF:

0.988

AC:

59685

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1323

2646

3970

5293

6616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<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:

0.991

AC:

150917

AN:

152310

Hom.:

74771

Cov.:

AF XY:

0.992

AC XY:

73851

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.997

AC:

41450

AN:

41566

American (AMR)

AF:

0.993

AC:

15176

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

3418

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5174

AN:

5174

South Asian (SAS)

AF:

0.999

AC:

4827

AN:

4832

European-Finnish (FIN)

AF:

0.992

AC:

10533

AN:

10618

Middle Eastern (MID)

AF:

1.00

AC:

292

AN:

292

European-Non Finnish (NFE)

AF:

0.985

AC:

67051

AN:

68042

Other (OTH)

AF:

0.991

AC:

2096

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.988

Hom.:

109209

Bravo

AF:

0.991

Asia WGS

AF:

0.999

AC:

3475

AN:

3478

EpiCase

AF:

0.985

EpiControl

AF:

0.987

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

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

-0.89

CADD

Benign

1.3

(source)

DANN

Benign

0.24

PhyloP100

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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