dbSNP rs11880388: DNMT1:c.3117-677C>T (chr19-10142897-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001130823.3(DNMT1):c.3117-677C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 157,454 control chromosomes in the GnomAD database, including 18,845 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 18235 hom., cov: 32)

Exomes 𝑓: 0.47 ( 610 hom. )

Consequence

DNMT1
NM_001130823.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.377

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DNMT1	NM_001130823.3 link	c.3117-677C>T	intron_variant	Intron 29 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 link	c.3069-677C>T	intron_variant	Intron 28 of 39		NP_001305659.1
DNMT1	NM_001379.4 link	c.3069-677C>T	intron_variant	Intron 28 of 39		NP_001370.1
DNMT1	NM_001318731.2 link	c.2754-677C>T	intron_variant	Intron 29 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.3117-677C>T		intron_variant	Intron 29 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

74009

AN:

151966

Hom.:

18241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.482

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.445

Gnomad EAS

AF:

0.327

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.483

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.501

Gnomad OTH

AF:

0.513

GnomAD4 exome

AF:

0.468

AC:

2515

AN:

5370

Hom.:

610

Cov.:

AF XY:

0.465

AC XY:

1338

AN XY:

2878

show subpopulations

African (AFR)

AF:

0.400

AC:

AN:

American (AMR)

AF:

0.490

AC:

695

AN:

1418

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

AN:

East Asian (EAS)

AF:

0.273

AC:

AN:

154

South Asian (SAS)

AF:

0.434

AC:

277

AN:

638

European-Finnish (FIN)

AF:

0.478

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.476

AC:

1371

AN:

2880

Other (OTH)

AF:

0.473

AC:

AN:

188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.487

AC:

74030

AN:

152084

Hom.:

18235

Cov.:

AF XY:

0.486

AC XY:

36146

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.481

AC:

19969

AN:

41490

American (AMR)

AF:

0.508

AC:

7764

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.445

AC:

1544

AN:

3472

East Asian (EAS)

AF:

0.327

AC:

1686

AN:

5162

South Asian (SAS)

AF:

0.473

AC:

2284

AN:

4826

European-Finnish (FIN)

AF:

0.483

AC:

5105

AN:

10566

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.501

AC:

34065

AN:

67970

Other (OTH)

AF:

0.509

AC:

1074

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1981

3962

5944

7925

9906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.464

Hom.:

6571

Bravo

AF:

0.492

Asia WGS

AF:

0.413

AC:

1436

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.1

(source)

DANN

Benign

0.66

PhyloP100

-0.38

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

Computational scores

Splicing

Publications

Other links and lift over