rs199473692

chr19-10155018-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001130823.3(DNMT1):c.1531T>C(p.Tyr511His) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y511C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 9.30

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 13 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 chr19-10155017-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.
• PP2: Missense variant where missense usually causes diseases, DNMT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 19-10155018-A-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.1531T>C	p.Tyr511His	missense_variant	20/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.1483T>C	p.Tyr495His	missense_variant	19/40
DNMT1	NM_001379.4	c.1483T>C	p.Tyr495His	missense_variant	19/40
DNMT1	NM_001318731.2	c.1168T>C	p.Tyr390His	missense_variant	20/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.1531T>C	p.Tyr511His	missense_variant	20/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2018

The Y511H pathogenic variant in the DNMT1 gene has been reported previously using alternate nomenclature (Y495H) in association with autosomal dominant hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The Y511H variant was reported in two brothers with hearing loss, peripheral sensory neuropathy with lesions leading toe amputations, tremor, cognitive and memory decline, psychiatric manifestations and seizures with similar symptoms reported in one son and in their father, paternal grandmother and paternal great grandmother (Klein et al., 2013). Baets et al. (2015), reported a kindred of 10 individuals across two generations with peripheral sensory neuropathy, foot ulcers, severe hearing loss, cognitive decline, psychiatric complaints, lymphoedema and cerebellar atrophy with molecular confirmation of the Y511H variant in the only two individuals available for testing. The Y511H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y511H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown the Y511H variant protein is mislocalized from the nucleus to the cytosol during the G2 phase, forming cytosolic aggegates that lead to early degradation and toxic cell stress (Baets et al., 2015). The Y511H variant is located in the TS domain, as are all other pathogenic variants in the DMNT1 gene, and the Y511 residue is a hotspot for mutation within the region, as another substitution at the same residue (Y511C) has been reported in the Human Gene Mutation Database in association with DMNT1-related disorders (Stenson et al., 2014). Therefore, we interpret Y511H as a pathogenic variant -

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	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	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		0.65		Gain of disorder (P = 0.0283);.;
MVP		0.97
MPC		2.5
ClinPred		0.98	D
GERP RS		6.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.86
gMVP		0.99

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: rs199473692; hg19: chr19-10265694;