chr19-10139794-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001130823.3(DNMT1):​c.3830G>T​(p.Arg1277Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

DNMT1
NM_001130823.3 missense

Scores

6
9
4

Clinical Significance

Not reported in ClinVar

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNMT1NM_001130823.3 linkc.3830G>T p.Arg1277Leu missense_variant 34/41 ENST00000359526.9 NP_001124295.1 P26358-2I6L9H2
DNMT1NM_001318730.2 linkc.3782G>T p.Arg1261Leu missense_variant 33/40 NP_001305659.1 P26358Q59FP7I6L9H2
DNMT1NM_001379.4 linkc.3782G>T p.Arg1261Leu missense_variant 33/40 NP_001370.1 P26358-1I6L9H2
DNMT1NM_001318731.2 linkc.3467G>T p.Arg1156Leu missense_variant 34/41 NP_001305660.1 P26358I6L9H2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMT1ENST00000359526.9 linkc.3830G>T p.Arg1277Leu missense_variant 34/411 NM_001130823.3 ENSP00000352516.3 P26358-2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152024
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152024
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.79
D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
1.5
L;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.65
Sift
Benign
0.063
T;T
Sift4G
Benign
0.080
T;T
Polyphen
0.98
D;P
Vest4
0.68
MutPred
0.65
Loss of MoRF binding (P = 0.1933);.;
MVP
0.88
MPC
1.9
ClinPred
0.99
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.44
gMVP
0.96

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.

Other links and lift over

dbSNP: rs774073234; hg19: chr19-10250470; API