rs1555690467

Variant names:

• chr19-10149565-G-A
• rs1555690467
• NM_001130823.3:c.2474C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001130823.3(DNMT1):​c.2474C>T​(p.Ser825Leu) 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. 12/21 in silico tools predict a damaging 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: 9.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2474C>T	p.Ser825Leu	missense_variant	Exon 26 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2426C>T	p.Ser809Leu	missense_variant	Exon 25 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.2426C>T	p.Ser809Leu	missense_variant	Exon 25 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.2111C>T	p.Ser704Leu	missense_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.2474C>T	p.Ser825Leu	missense_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

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 539609). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 825 of the DNMT1 protein (p.Ser825Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.48		Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.98
MPC		2.0
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.89

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: rs1555690467; hg19: chr19-10260241; COSMIC: COSV61578749; COSMIC: COSV61578749;