19-10154917-G-T

Position:

chr19-10154917-G-T

Variant summary

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

The NM_001130823.3(DNMT1):c.1632C>A(p.Ile544Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 1,614,142 control chromosomes in the GnomAD database, including 6,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 462 hom., cov: 32)

Exomes 𝑓: 0.086 ( 5797 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.17

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=-0.54).

BP6

Variant 19-10154917-G-T is Benign according to our data. Variant chr19-10154917-G-T is described in ClinVar as [Benign]. Clinvar id is 137134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10154917-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=3.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 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.1632C>A	p.Ile544Ile	synonymous_variant	20/41	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 linkuse as main transcript	c.1584C>A	p.Ile528Ile	synonymous_variant	19/40		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 linkuse as main transcript	c.1584C>A	p.Ile528Ile	synonymous_variant	19/40		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 linkuse as main transcript	c.1269C>A	p.Ile423Ile	synonymous_variant	20/41		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.1632C>A	p.Ile544Ile	synonymous_variant	20/41	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.0682

AC:

10380

AN:

152150

Hom.:

462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0464

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0683

Gnomad FIN

AF:

0.0767

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0973

Gnomad OTH

AF:

0.0603

GnomAD3 exomes

AF:

0.0708

AC:

17815

AN:

251480

Hom.:

768

AF XY:

0.0739

AC XY:

10049

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0356

Gnomad AMR exome

AF:

0.0312

Gnomad ASJ exome

AF:

0.0635

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0743

Gnomad FIN exome

AF:

0.0838

Gnomad NFE exome

AF:

0.0964

Gnomad OTH exome

AF:

0.0740

GnomAD4 exome

AF:

0.0860

AC:

125773

AN:

1461874

Hom.:

5797

Cov.:

AF XY:

0.0860

AC XY:

62553

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0331

Gnomad4 AMR exome

AF:

0.0339

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0747

Gnomad4 FIN exome

AF:

0.0840

Gnomad4 NFE exome

AF:

0.0950

Gnomad4 OTH exome

AF:

0.0748

GnomAD4 genome

AF:

0.0682

AC:

10384

AN:

152268

Hom.:

462

Cov.:

AF XY:

0.0678

AC XY:

5045

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0355

Gnomad4 AMR

AF:

0.0463

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0686

Gnomad4 FIN

AF:

0.0767

Gnomad4 NFE

AF:

0.0974

Gnomad4 OTH

AF:

0.0601

Alfa

AF:

0.0849

Hom.:

317

Bravo

AF:

0.0635

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0935

EpiControl

AF:

0.0944

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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