rs397509393

Variant names:

• chr19-10154604-C-G
• rs397509393
• NM_001130823.3:c.1814G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10154604-C-G
• chr19-10154604-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001130823.3(DNMT1):​c.1814G>C​(p.Gly605Ala) 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 (★). Synonymous variant affecting the same amino acid position (i.e. G605G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.72
• Publications: 13 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 19-10154604-C-G is Pathogenic according to our data. Variant chr19-10154604-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 50921.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1814G>C	p.Gly605Ala	missense_variant	Exon 21 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1766G>C	p.Gly589Ala	missense_variant	Exon 20 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.1766G>C	p.Gly589Ala	missense_variant	Exon 20 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.1451G>C	p.Gly484Ala	missense_variant	Exon 21 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1814G>C	p.Gly605Ala	missense_variant	Exon 21 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 90

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant cerebellar ataxia, deafness and narcolepsy Pathogenic:2

Jan 10, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.69		Loss of sheet (P = 0.0063);.;
MVP		0.70
MPC		2.3
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397509393; hg19: chr19-10265280;