rs61750051

Positions:

• chr19-10149576-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001130823.3(DNMT1):​c.2463C>T​(p.Leu821Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,613,598 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (25 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.40

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-10149576-G-A is Benign according to our data. Variant chr19-10149576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 327901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10149576-G-A is described in Lovd as [Likely_benign]. Variant chr19-10149576-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BS2: High AC in GnomAd4 at 534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2463C>T	p.Leu821Leu	synonymous_variant	26/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2415C>T	p.Leu805Leu	synonymous_variant	25/40		NP_001305659.1
DNMT1	NM_001379.4	c.2415C>T	p.Leu805Leu	synonymous_variant	25/40		NP_001370.1
DNMT1	NM_001318731.2	c.2100C>T	p.Leu700Leu	synonymous_variant	26/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.2463C>T	p.Leu821Leu	synonymous_variant	26/41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 534 AN: 151600 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00383 AC: 962 AN: 251182 Hom.: 8 AF XY: 0.00401 AC XY: 545 AN XY: 135758

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00279 AC: 4082 AN: 1461880 Hom.: 25 Cov.: 32 AF XY: 0.00292 AC XY: 2121 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00214

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00352 AC: 534 AN: 151718 Hom.: 5 Cov.: 32 AF XY: 0.00362 AC XY: 268 AN XY: 74114

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00523 Hom.: 3

Bravo AF: 0.00180

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DNMT1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Hereditary sensory neuropathy-deafness-dementia syndrome;C3807295:Autosomal dominant cerebellar ataxia, deafness and narcolepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.34
DANN	Benign	0.68

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: rs61750051; hg19: chr19-10260252; COSMIC: COSV61584531; COSMIC: COSV61584531;