rs199473690

chr19-10155017-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001130823.3(DNMT1):c.1532A>G(p.Tyr511Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y511H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:2
• Conservation: PhyloP100: 7.99

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001130823.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-10155018-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 162188.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DNMT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-10155017-T-C is Pathogenic according to our data. Variant chr19-10155017-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10155017-T-C is described in Lovd as [Pathogenic]. Variant chr19-10155017-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.1532A>G	p.Tyr511Cys	missense_variant	20/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.1484A>G	p.Tyr495Cys	missense_variant	19/40
DNMT1	NM_001379.4	c.1484A>G	p.Tyr495Cys	missense_variant	19/40
DNMT1	NM_001318731.2	c.1169A>G	p.Tyr390Cys	missense_variant	20/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.1532A>G	p.Tyr511Cys	missense_variant	20/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2013	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jul 30, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 511 of the DNMT1 protein (p.Tyr511Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary sensory neuropathy, dementia and hearing loss (PMID: 21532572, 25326637, 25678562). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Tyr495Cys. ClinVar contains an entry for this variant (Variation ID: 29682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT1 function (PMID: 21532572, 28334952). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant cerebellar ataxia, deafness and narcolepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence that the variant has a damaging effect on the gene or gene product (PMID: 21532572). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with solid evidence (ClinVar ID: VCV000029682). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21532572 , 23365052). A different missense change at the same codon (p.Tyr511His) has been reported to be associated with DNMT1-related disorder (ClinVar ID: VCV000162188 / PMID: 23365052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2021

Published functional studies demonstrate a damaging effect showing degradation compared to wild-type DNMT protein (Baets et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21532572, 25678562, 25942534, 23521649, 26747177, 23365052) -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.55		Loss of phosphorylation at Y495 (P = 0.0337);.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199473690; hg19: chr19-10265693;