Genetic Variant NM_001130823.3:c.2894+810C>T (chr19-10145541-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.2894+810C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,238 control chromosomes in the GnomAD database, including 1,402 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 0.11 ( 1402 hom., cov: 32)

Consequence

DNMT1
NM_001130823.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.725

Publications

11 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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3 link	c.2894+810C>T	intron_variant	Intron 28 of 40	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 link	c.2846+810C>T	intron_variant	Intron 27 of 39		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 link	c.2846+810C>T	intron_variant	Intron 27 of 39		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 link	c.2531+810C>T	intron_variant	Intron 28 of 40		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.2894+810C>T		intron_variant	Intron 28 of 40	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17042

AN:

152120

Hom.:

1399

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.0926

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0626

Gnomad OTH

AF:

0.108

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.112

AC:

17075

AN:

152238

Hom.:

1402

Cov.:

AF XY:

0.118

AC XY:

8796

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.126

AC:

5220

AN:

41550

American (AMR)

AF:

0.188

AC:

2875

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

373

AN:

3468

East Asian (EAS)

AF:

0.394

AC:

2033

AN:

5156

South Asian (SAS)

AF:

0.209

AC:

1007

AN:

4828

European-Finnish (FIN)

AF:

0.0926

AC:

983

AN:

10616

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0626

AC:

4259

AN:

68028

Other (OTH)

AF:

0.108

AC:

228

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

737

1474

2212

2949

3686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.0755

Hom.:

719

Bravo

AF:

0.121

Asia WGS

AF:

0.259

AC:

900

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.80

(source)

DANN

Benign

0.75

PhyloP100

-0.72

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over