Menu
GeneBe

19-10133671-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001130823.3(DNMT1):c.4895A>G(p.Asp1632Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1632H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

DNMT1
NM_001130823.3 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, DNMT1
BP4
Computational evidence support a benign effect (MetaRNN=0.16015816).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNMT1NM_001130823.3 linkuse as main transcriptc.4895A>G p.Asp1632Gly missense_variant 41/41 ENST00000359526.9
DNMT1NM_001318730.2 linkuse as main transcriptc.4856A>G p.Asp1619Gly missense_variant 40/40
DNMT1NM_001379.4 linkuse as main transcriptc.4847A>G p.Asp1616Gly missense_variant 40/40
DNMT1NM_001318731.2 linkuse as main transcriptc.4532A>G p.Asp1511Gly missense_variant 41/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNMT1ENST00000359526.9 linkuse as main transcriptc.4895A>G p.Asp1632Gly missense_variant 41/411 NM_001130823.3 P26358-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 29, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1632 of the DNMT1 protein (p.Asp1632Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.34
Cadd
Benign
21
Dann
Uncertain
0.99
DEOGEN2
Benign
0.42
T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.70
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;.
MutationTaster
Benign
0.83
N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.021
D;D
Polyphen
0.24
B;B
Vest4
0.37
MVP
0.66
MPC
1.3
ClinPred
0.76
D
GERP RS
2.7
Varity_R
0.21
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10244347; API