19-10146517-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001130823.3(DNMT1):c.2728G>A(p.Val910Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V910L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.876

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09242216).

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.2728G>A	p.Val910Met	missense	Exon 28 of 41	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.2680G>A	p.Val894Met	missense	Exon 27 of 40	NP_001305659.1
DNMT1	NM_001379.4		c.2680G>A	p.Val894Met	missense	Exon 27 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.2728G>A	p.Val910Met	missense	Exon 28 of 41	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.2680G>A	p.Val894Met	missense	Exon 27 of 40	ENSP00000345739.3	P26358-1
DNMT1	ENST00000592705.5	TSL:1	n.*2418G>A		non_coding_transcript_exon	Exon 28 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.37

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0075

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

0.88

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.26

REVEL

Benign

0.072

Sift

Benign

0.22

Sift4G

Benign

0.24

Polyphen

0.0080

Vest4

0.14

MutPred

0.43

Gain of catalytic residue at V894 (P = 0.0025)

MVP

0.34

MPC

1.0

ClinPred

0.074

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.11

gMVP

0.18

Mutation Taster

=88/12

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over