19-10180797-C-T

Position:

chr19-10180797-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001130823.3(DNMT1):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,950 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 9 hom., cov: 31)

Exomes 𝑓: 0.011 ( 113 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.392

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 -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT1. . Gene score misZ 4.9903 (greater than the threshold 3.09). Trascript score misZ 7.3302 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory neuropathy-deafness-dementia syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023405552).

BP6

Variant 19-10180797-C-T is Benign according to our data. Variant chr19-10180797-C-T is described in ClinVar as [Benign]. Clinvar id is 137132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180797-C-T is described in Lovd as [Benign]. Variant chr19-10180797-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/41	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/40		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/40		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 linkuse as main transcript	c.-118G>A		5_prime_UTR_variant	3/41		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.206G>A	p.Arg69His	missense_variant	3/41	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.00936

AC:

1423

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00302

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.0312

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.0101

AC:

2549

AN:

251240

Hom.:

AF XY:

0.0101

AC XY:

1377

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.0316

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0113

AC:

16539

AN:

1461730

Hom.:

113

Cov.:

AF XY:

0.0111

AC XY:

8049

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00260

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00924

GnomAD4 genome

AF:

0.00935

AC:

1424

AN:

152220

Hom.:

Cov.:

AF XY:

0.00956

AC XY:

712

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00374

Gnomad4 FIN

AF:

0.0312

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00700

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00908

AC:

1102

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DNMT1: BP4, BS1, BS2 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.35

T;.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

0.080

N;N;.

REVEL

Benign

0.040

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.37

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.11

MPC

0.51

ClinPred

0.0085

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.046

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