chr19-10156401-T-C

Position:

chr19-10156401-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001130823.3(DNMT1):c.1389A>G(p.Pro463Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,605,870 control chromosomes in the GnomAD database, including 205,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 19965 hom., cov: 29)

Exomes 𝑓: 0.50 ( 185874 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -8.10

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 links:

DNMT1 (HGNC:):

DNMT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 19-10156401-T-C is Benign according to our data. Variant chr19-10156401-T-C is described in ClinVar as [Benign]. Clinvar id is 257536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10156401-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-8.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3 linkuse as main transcript	c.1389A>G	p.Pro463Pro	synonymous_variant	18/41	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 linkuse as main transcript	c.1341A>G	p.Pro447Pro	synonymous_variant	17/40		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 linkuse as main transcript	c.1341A>G	p.Pro447Pro	synonymous_variant	17/40		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 linkuse as main transcript	c.1026A>G	p.Pro342Pro	synonymous_variant	18/41		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 linkuse as main transcript	c.1389A>G	p.Pro463Pro	synonymous_variant	18/41	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.510

AC:

77266

AN:

151414

Hom.:

19932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.508

Gnomad AMI

AF:

0.559

Gnomad AMR

AF:

0.493

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.487

GnomAD3 exomes

AF:

0.519

AC:

130376

AN:

251354

Hom.:

34234

AF XY:

0.518

AC XY:

70358

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.512

Gnomad AMR exome

AF:

0.484

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.695

Gnomad SAS exome

AF:

0.539

Gnomad FIN exome

AF:

0.521

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.513

GnomAD4 exome

AF:

0.504

AC:

732721

AN:

1454336

Hom.:

185874

Cov.:

AF XY:

0.505

AC XY:

365549

AN XY:

723916

show subpopulations

Gnomad4 AFR exome

AF:

0.510

Gnomad4 AMR exome

AF:

0.482

Gnomad4 ASJ exome

AF:

0.554

Gnomad4 EAS exome

AF:

0.622

Gnomad4 SAS exome

AF:

0.537

Gnomad4 FIN exome

AF:

0.524

Gnomad4 NFE exome

AF:

0.495

Gnomad4 OTH exome

AF:

0.512

GnomAD4 genome

AF:

0.511

AC:

77363

AN:

151534

Hom.:

19965

Cov.:

AF XY:

0.512

AC XY:

37910

AN XY:

74036

show subpopulations

Gnomad4 AFR

AF:

0.509

Gnomad4 AMR

AF:

0.493

Gnomad4 ASJ

AF:

0.556

Gnomad4 EAS

AF:

0.675

Gnomad4 SAS

AF:

0.547

Gnomad4 FIN

AF:

0.515

Gnomad4 NFE

AF:

0.497

Gnomad4 OTH

AF:

0.491

Alfa

AF:

0.500

Hom.:

44350

Bravo

AF:

0.505

Asia WGS

AF:

0.603

AC:

2096

AN:

3478

EpiCase

AF:

0.491

EpiControl

AF:

0.487

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal dominant cerebellar ataxia, deafness and narcolepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.31

DANN

Benign

0.36

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over