19-10154572-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001130823.3(DNMT1):c.1832+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,734 control chromosomes in the GnomAD database, including 206,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 19882 hom., cov: 31)

Exomes 𝑓: 0.50 ( 186652 hom. )

Consequence

DNMT1
NM_001130823.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.19

Publications

43 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 19-10154572-T-C is Benign according to our data. Variant chr19-10154572-T-C is described in ClinVar as Benign. ClinVar VariationId is 257538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3 link	c.1832+14A>G	intron_variant	Intron 21 of 40	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 link	c.1784+14A>G	intron_variant	Intron 20 of 39		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 link	c.1784+14A>G	intron_variant	Intron 20 of 39		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 link	c.1469+14A>G	intron_variant	Intron 21 of 40		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.1832+14A>G		intron_variant	Intron 21 of 40	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

77170

AN:

151830

Hom.:

19850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.559

Gnomad AMR

AF:

0.492

Gnomad ASJ

AF:

0.552

Gnomad EAS

AF:

0.676

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.516

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.484

GnomAD2 exomes

AF:

0.518

AC:

129746

AN:

250402

AF XY:

0.517

show subpopulations

Gnomad AFR exome

AF:

0.506

Gnomad AMR exome

AF:

0.484

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.521

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.512

GnomAD4 exome

AF:

0.504

AC:

736772

AN:

1461786

Hom.:

186652

Cov.:

AF XY:

0.505

AC XY:

367328

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.503

AC:

16839

AN:

33480

American (AMR)

AF:

0.482

AC:

21576

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

14422

AN:

26136

East Asian (EAS)

AF:

0.626

AC:

24836

AN:

39700

South Asian (SAS)

AF:

0.537

AC:

46352

AN:

86258

European-Finnish (FIN)

AF:

0.524

AC:

27941

AN:

53342

Middle Eastern (MID)

AF:

0.562

AC:

3244

AN:

5768

European-Non Finnish (NFE)

AF:

0.495

AC:

550649

AN:

1111984

Other (OTH)

AF:

0.512

AC:

30913

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

24502

49004

73506

98008

122510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16228

32456

48684

64912

81140

<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:

0.508

AC:

77265

AN:

151948

Hom.:

19882

Cov.:

AF XY:

0.510

AC XY:

37890

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.502

AC:

20795

AN:

41428

American (AMR)

AF:

0.492

AC:

7499

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

1915

AN:

3468

East Asian (EAS)

AF:

0.676

AC:

3487

AN:

5160

South Asian (SAS)

AF:

0.547

AC:

2636

AN:

4818

European-Finnish (FIN)

AF:

0.516

AC:

5453

AN:

10564

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.497

AC:

33780

AN:

67954

Other (OTH)

AF:

0.489

AC:

1033

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1943

3886

5830

7773

9716

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:

0.502

Hom.:

3641

Bravo

AF:

0.503

Asia WGS

AF:

0.604

AC:

2098

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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

- -

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

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 12, 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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.90

CADD

Benign

0.010

(source)

DANN

Benign

0.35

PhyloP100

-2.2

Mutation Taster

=100/0

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