Genetic Variant DNMT1:c.81-2371C>T (chr19-10184448-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.81-2371C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,002 control chromosomes in the GnomAD database, including 9,539 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 0.34 ( 9539 hom., cov: 31)

Exomes 𝑓: 0.38 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.623

Publications

23 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:

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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=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3 link	c.81-2371C>T	intron_variant	Intron 1 of 40	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 link	c.81-2371C>T	intron_variant	Intron 1 of 39		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 link	c.81-2371C>T	intron_variant	Intron 1 of 39		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 link	c.-243-2371C>T	intron_variant	Intron 1 of 40		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.81-2371C>T		intron_variant	Intron 1 of 40	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.343

AC:

52162

AN:

151868

Hom.:

9540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.341

GnomAD4 exome

AF:

0.375

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.343

AC:

52178

AN:

151986

Hom.:

9539

Cov.:

AF XY:

0.339

AC XY:

25154

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.244

AC:

10123

AN:

41446

American (AMR)

AF:

0.281

AC:

4287

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

1538

AN:

3468

East Asian (EAS)

AF:

0.238

AC:

1234

AN:

5174

South Asian (SAS)

AF:

0.326

AC:

1571

AN:

4826

European-Finnish (FIN)

AF:

0.368

AC:

3879

AN:

10542

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.416

AC:

28254

AN:

67954

Other (OTH)

AF:

0.345

AC:

729

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1710

3420

5131

6841

8551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.388

Hom.:

7986

Bravo

AF:

0.328

Asia WGS

AF:

0.279

AC:

970

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.60

(source)

DANN

Benign

0.46

PhyloP100

-0.62

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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chr19-10184448-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over