19-10173163-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130823.3(DNMT1):​c.695C>A​(p.Pro232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.367
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.059997916).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNMT1NM_001130823.3 linkc.695C>A p.Pro232Gln missense_variant Exon 9 of 41 ENST00000359526.9 NP_001124295.1 P26358-2I6L9H2
DNMT1NM_001318730.2 linkc.647C>A p.Pro216Gln missense_variant Exon 8 of 40 NP_001305659.1 P26358Q59FP7I6L9H2
DNMT1NM_001379.4 linkc.647C>A p.Pro216Gln missense_variant Exon 8 of 40 NP_001370.1 P26358-1I6L9H2
DNMT1NM_001318731.2 linkc.332C>A p.Pro111Gln missense_variant Exon 9 of 41 NP_001305660.1 P26358I6L9H2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNMT1ENST00000359526.9 linkc.695C>A p.Pro232Gln missense_variant Exon 9 of 41 1 NM_001130823.3 ENSP00000352516.3 P26358-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
3.9
DANN
Benign
0.88
DEOGEN2
Benign
0.40
T;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.031
N
LIST_S2
Benign
0.63
T;T;T
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.060
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.52
N;N;.
REVEL
Benign
0.011
Sift
Benign
0.059
T;T;.
Sift4G
Benign
0.61
T;T;T
Polyphen
0.34
B;P;.
Vest4
0.29
MutPred
0.21
Gain of helix (P = 0.0199);.;.;
MVP
0.35
MPC
0.38
ClinPred
0.080
T
GERP RS
0.031
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.1
Varity_R
0.026
gMVP
0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10283839; COSMIC: COSV61578601; COSMIC: COSV61578601; API