19-10168330-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001130823.3(DNMT1):​c.803C>G​(p.Pro268Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 missense, splice_region

Scores

2
17
Splicing: ADA: 0.00006190
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.16
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08798754).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNMT1NM_001130823.3 linkc.803C>G p.Pro268Arg missense_variant, splice_region_variant Exon 10 of 41 ENST00000359526.9 NP_001124295.1 P26358-2I6L9H2
DNMT1NM_001318730.2 linkc.755C>G p.Pro252Arg missense_variant, splice_region_variant Exon 9 of 40 NP_001305659.1 P26358Q59FP7I6L9H2
DNMT1NM_001379.4 linkc.755C>G p.Pro252Arg missense_variant, splice_region_variant Exon 9 of 40 NP_001370.1 P26358-1I6L9H2
DNMT1NM_001318731.2 linkc.440C>G p.Pro147Arg missense_variant, splice_region_variant Exon 10 of 41 NP_001305660.1 P26358I6L9H2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNMT1ENST00000359526.9 linkc.803C>G p.Pro268Arg missense_variant, splice_region_variant Exon 10 of 41 1 NM_001130823.3 ENSP00000352516.3 P26358-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251446
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727230
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
0.078
DANN
Benign
0.32
DEOGEN2
Uncertain
0.45
T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.46
T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.088
T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.69
N;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.46
N;N
REVEL
Benign
0.045
Sift
Benign
0.21
T;T
Sift4G
Benign
0.64
T;T
Polyphen
0.64
P;P
Vest4
0.12
MutPred
0.31
Gain of MoRF binding (P = 0.0059);.;
MVP
0.68
MPC
0.43
ClinPred
0.19
T
GERP RS
-6.4
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.10
gMVP
0.084

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000062
dbscSNV1_RF
Benign
0.15
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: rs779634956; hg19: chr19-10279006; API