19-10149656-C-T

Variant names:

• chr19-10149656-C-T
• rs1555690511
• NM_001130823.3:c.2383G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130823.3(DNMT1):​c.2383G>A​(p.Val795Ile) variant causes a missense, splice region 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. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V795V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT1 NM_001130823.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002375
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

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]

DNMT1 Gene-Disease associations (from GenCC):

• autosomal dominant cerebellar ataxia, deafness and narcolepsy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20705634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2383G>A	p.Val795Ile	missense_variant, splice_region_variant	Exon 26 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2335G>A	p.Val779Ile	missense_variant, splice_region_variant	Exon 25 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.2335G>A	p.Val779Ile	missense_variant, splice_region_variant	Exon 25 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.2020G>A	p.Val674Ile	missense_variant, splice_region_variant	Exon 26 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.2383G>A	p.Val795Ile	missense_variant, splice_region_variant	Exon 26 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Jun 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on DNMT1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a DNMT1-related disease. This sequence change replaces valine with isoleucine at codon 795 of the DNMT1 protein (p.Val795Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.39	N;.
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.17
Sift	Benign	0.31	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.33	B;P
Vest4		0.30
MutPred		0.47		Gain of helix (P = 0.062);.;
MVP		0.71
MPC		0.91
ClinPred		0.82	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.049
gMVP		0.52
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.026
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

Other links and lift over

dbSNP: rs1555690511; hg19: chr19-10260332;