chr19-10139794-C-T

Position:

chr19-10139794-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001130823.3(DNMT1):c.3830G>A(p.Arg1277Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,592,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

BS2

High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNMT1	NM_001130823.3 linkuse as main transcript	c.3830G>A	p.Arg1277Gln	missense_variant	34/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 linkuse as main transcript	c.3782G>A	p.Arg1261Gln	missense_variant	33/40		NP_001305659.1
DNMT1	NM_001379.4 linkuse as main transcript	c.3782G>A	p.Arg1261Gln	missense_variant	33/40		NP_001370.1
DNMT1	NM_001318731.2 linkuse as main transcript	c.3467G>A	p.Arg1156Gln	missense_variant	34/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 linkuse as main transcript	c.3830G>A	p.Arg1277Gln	missense_variant	34/41	1	NM_001130823.3	ENSP00000352516		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000385

AC:

AN:

207858

Hom.:

AF XY:

0.0000536

AC XY:

AN XY:

111856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000437

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1440312

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

714516

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000249

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000479

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000245

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000621

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

The p.R1261Q variant (also known as c.3782G>A), located in coding exon 33 of the DNMT1 gene, results from a G to A substitution at nucleotide position 3782. The arginine at codon 1261 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary sensory neuropathy-deafness-dementia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1277 of the DNMT1 protein (p.Arg1277Gln). This variant is present in population databases (rs774073234, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.98

D;D

Vest4

0.56

MVP

0.87

MPC

1.8

ClinPred

0.33

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.26

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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