dbSNP rs4804494: DNMT1:c.80+2047A>C (chr19-10192773-T-G) – 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.80+2047A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 151,888 control chromosomes in the GnomAD database, including 1,498 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 0.12 ( 1498 hom., cov: 31)

Consequence

DNMT1
NM_001130823.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0590

Publications

3 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 = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DNMT1	NM_001130823.3 link	c.80+2047A>C	intron_variant	Intron 1 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 link	c.80+2047A>C	intron_variant	Intron 1 of 39		NP_001305659.1
DNMT1	NM_001379.4 link	c.80+2047A>C	intron_variant	Intron 1 of 39		NP_001370.1
DNMT1	NM_001318731.2 link	c.-244+2047A>C	intron_variant	Intron 1 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.80+2047A>C		intron_variant	Intron 1 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17788

AN:

151770

Hom.:

1493

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.398

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.0928

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0627

Gnomad OTH

AF:

0.112

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

GnomAD4 genome

AF:

0.117

AC:

17836

AN:

151888

Hom.:

1498

Cov.:

AF XY:

0.123

AC XY:

9127

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.143

AC:

5943

AN:

41418

American (AMR)

AF:

0.189

AC:

2881

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

375

AN:

3466

East Asian (EAS)

AF:

0.398

AC:

2055

AN:

5158

South Asian (SAS)

AF:

0.209

AC:

1004

AN:

4814

European-Finnish (FIN)

AF:

0.0928

AC:

980

AN:

10556

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0628

AC:

4263

AN:

67934

Other (OTH)

AF:

0.112

AC:

236

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

765

1530

2296

3061

3826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0852

Hom.:

136

Bravo

AF:

0.127

Asia WGS

AF:

0.264

AC:

919

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

3.7

(source)

DANN

Benign

0.73

PhyloP100

-0.059

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