dbSNP rs721186: DNMT1:p.Thr594Thr (chr19-10154636-T-C) – ACMG Classification: Benign (-21 pts)

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: 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 -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.

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.1782A>G	p.Thr594Thr	synonymous	Exon 21 of 41	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.1734A>G	p.Thr578Thr	synonymous	Exon 20 of 40	NP_001305659.1
DNMT1	NM_001379.4		c.1734A>G	p.Thr578Thr	synonymous	Exon 20 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.1782A>G	p.Thr594Thr	synonymous	Exon 21 of 41	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.1734A>G	p.Thr578Thr	synonymous	Exon 20 of 40	ENSP00000345739.3	P26358-1
DNMT1	ENST00000592705.5	TSL:1	n.*1472A>G		non_coding_transcript_exon	Exon 21 of 41	ENSP00000466657.1	K7EMU8

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hereditary sensory neuropathy-deafness-dementia syndrome (3)

not provided (2)

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (1)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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