rs368960099

Variant names:

• chr19-10166633-C-G
• rs368960099
• NM_001130823.3:c.856G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10166633-C-G
• chr19-10166633-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130823.3(DNMT1):​c.856G>C​(p.Val286Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.565

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]

ACMG classification

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=0.049307674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.856G>C	p.Val286Leu	missense_variant	Exon 11 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.808G>C	p.Val270Leu	missense_variant	Exon 10 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.808G>C	p.Val270Leu	missense_variant	Exon 10 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.493G>C	p.Val165Leu	missense_variant	Exon 11 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.856G>C	p.Val286Leu	missense_variant	Exon 11 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 14, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25942534, 25678562, 23521649, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.11
DANN	Benign	0.36
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.023
Sift	Benign	0.21	T;T
Sift4G	Benign	0.90	T;T
Polyphen		0.0	B;B
Vest4		0.079
MutPred		0.20		Gain of helix (P = 0.132);.;
MVP		0.37
MPC		0.40
ClinPred		0.080	T
GERP RS		-3.1
Varity_R		0.022
gMVP		0.042

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

LitVar

Other links and lift over

dbSNP: rs368960099; hg19: chr19-10277309;