rs150999369

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001130823.3(DNMT1):c.731G>A(p.Gly244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,992 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00064 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00052 ( 5 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.842

Publications

4 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072378516).

BP6

Variant 19-10173127-C-T is Benign according to our data. Variant chr19-10173127-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 234309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 97 AD gene.

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.731G>A	p.Gly244Glu	missense	Exon 9 of 41	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.683G>A	p.Gly228Glu	missense	Exon 8 of 40	NP_001305659.1
DNMT1	NM_001379.4		c.683G>A	p.Gly228Glu	missense	Exon 8 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.731G>A	p.Gly244Glu	missense	Exon 9 of 41	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.683G>A	p.Gly228Glu	missense	Exon 8 of 40	ENSP00000345739.3	P26358-1
DNMT1	ENST00000592705.5	TSL:1	n.*421G>A		non_coding_transcript_exon	Exon 9 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00113

AC:

284

AN:

251452

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000522

AC:

763

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

393

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00181

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

448

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1112008

Other (OTH)

AF:

0.00169

AC:

102

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000638

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41410

American (AMR)

AF:

0.000459

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000991

Hom.:

Bravo

AF:

0.000759

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000923

AC:

112

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary sensory neuropathy-deafness-dementia syndrome (2)

Hereditary sensory neuropathy-deafness-dementia syndrome;C4302668:Autosomal dominant cerebellar ataxia, deafness and narcolepsy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.40

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.53

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0072

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

0.84

PrimateAI

Benign

0.40

PROVEAN

Benign

0.46

REVEL

Benign

0.032

Sift

Uncertain

0.0050

Sift4G

Benign

0.91

Polyphen

0.79

Vest4

0.25

MVP

0.37

MPC

0.53

ClinPred

0.026

GERP RS

0.79

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.7

Varity_R

0.073

gMVP

0.16

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over