rs16999593

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.290A>G(p.His97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 1,614,168 control chromosomes in the GnomAD database, including 1,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H97Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 142 hom., cov: 31)

Exomes 𝑓: 0.0079 ( 892 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0510

Publications

69 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

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 (MetaRNN=0.0013153255).

BP6

Variant 19-10180505-T-C is Benign according to our data. Variant chr19-10180505-T-C is described in ClinVar as Benign. ClinVar VariationId is 257539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT1	NM_001130823.3	MANE Select	c.290A>G	p.His97Arg	missense	Exon 4 of 41	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.290A>G	p.His97Arg	missense	Exon 4 of 40	NP_001305659.1
DNMT1	NM_001379.4		c.290A>G	p.His97Arg	missense	Exon 4 of 40	NP_001370.1	P26358-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.290A>G	p.His97Arg	missense	Exon 4 of 41	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.290A>G	p.His97Arg	missense	Exon 4 of 40	ENSP00000345739.3	P26358-1
DNMT1	ENST00000592705.5	TSL:1	n.250A>G		non_coding_transcript_exon	Exon 4 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1818

AN:

152156

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0245

AC:

6155

AN:

251494

AF XY:

0.0211

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.0567

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00786

AC:

11484

AN:

1461894

Hom.:

892

Cov.:

AF XY:

0.00755

AC XY:

5490

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00179

AC:

AN:

33480

American (AMR)

AF:

0.0548

AC:

2450

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26136

East Asian (EAS)

AF:

0.189

AC:

7487

AN:

39700

South Asian (SAS)

AF:

0.00523

AC:

451

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000161

AC:

179

AN:

1112012

Other (OTH)

AF:

0.0135

AC:

815

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

754

1508

2262

3016

3770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.0120

AC:

1822

AN:

152274

Hom.:

142

Cov.:

AF XY:

0.0130

AC XY:

966

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41568

American (AMR)

AF:

0.0397

AC:

607

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.198

AC:

1026

AN:

5170

South Asian (SAS)

AF:

0.00767

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68026

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00726

Hom.:

242

Bravo

AF:

0.0160

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0217

AC:

2637

Asia WGS

AF:

0.0780

AC:

272

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Hereditary sensory neuropathy-deafness-dementia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.051

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.0

REVEL

Benign

0.021

Sift

Benign

0.88

Sift4G

Benign

0.72

Polyphen

0.49

Vest4

0.27

MPC

1.0

ClinPred

0.0067

GERP RS

2.1

PromoterAI

-0.0049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over