chr19-10139794-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1277R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

2
11
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.43

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6
Variant 19-10139794-C-T is Benign according to our data. Variant chr19-10139794-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 576485.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNMT1NM_001130823.3 linkc.3830G>A p.Arg1277Gln missense_variant Exon 34 of 41 ENST00000359526.9 NP_001124295.1 P26358-2I6L9H2
DNMT1NM_001318730.2 linkc.3782G>A p.Arg1261Gln missense_variant Exon 33 of 40 NP_001305659.1 P26358Q59FP7I6L9H2
DNMT1NM_001379.4 linkc.3782G>A p.Arg1261Gln missense_variant Exon 33 of 40 NP_001370.1 P26358-1I6L9H2
DNMT1NM_001318731.2 linkc.3467G>A p.Arg1156Gln missense_variant Exon 34 of 41 NP_001305660.1 P26358I6L9H2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNMT1ENST00000359526.9 linkc.3830G>A p.Arg1277Gln missense_variant Exon 34 of 41 1 NM_001130823.3 ENSP00000352516.3 P26358-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152024
Hom.:
0
Cov.:
33
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
GnomAD2 exomes
AF:
0.0000385
AC:
8
AN:
207858
AF XY:
0.0000536
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000437
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000229
AC:
33
AN:
1440312
Hom.:
0
Cov.:
33
AF XY:
0.0000210
AC XY:
15
AN XY:
714516
show subpopulations
African (AFR)
AF:
0.0000301
AC:
1
AN:
33268
American (AMR)
AF:
0.0000249
AC:
1
AN:
40088
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25576
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38968
South Asian (SAS)
AF:
0.0000479
AC:
4
AN:
83422
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51832
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5732
European-Non Finnish (NFE)
AF:
0.0000245
AC:
27
AN:
1101814
Other (OTH)
AF:
0.00
AC:
0
AN:
59612
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152024
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74268
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41410
American (AMR)
AF:
0.00
AC:
0
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4788
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.608
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000621
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 14, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Feb 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

not specified Benign:1
Feb 16, 2025
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Benign
1.9
L;.
PhyloP100
5.4
PrimateAI
Uncertain
0.68
T
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
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.26
gMVP
0.91
Mutation Taster
=63/37
polymorphism

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

Other links and lift over

dbSNP: rs774073234; hg19: chr19-10250470; COSMIC: COSV100532862; COSMIC: COSV100532862; API