19-10154572-T-C

Variant names:

• chr19-10154572-T-C
• rs2114724
• NM_001130823.3:c.1832+14A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.1832+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,734 control chromosomes in the GnomAD database, including 206,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19882 hom., cov: 31)
  • Exomes 𝑓: 0.50 (186652 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.19

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10154572-T-C is Benign according to our data. Variant chr19-10154572-T-C is described in ClinVar as [Benign]. Clinvar id is 257538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10154572-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1832+14A>G		intron_variant	Intron 21 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1784+14A>G		intron_variant	Intron 20 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.1784+14A>G		intron_variant	Intron 20 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.1469+14A>G		intron_variant	Intron 21 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1832+14A>G		intron_variant	Intron 21 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77170 AN: 151830 Hom.: 19850 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.484

GnomAD3 exomes AF: 0.518 AC: 129746 AN: 250402 Hom.: 34018 AF XY: 0.517 AC XY: 70067 AN XY: 135428

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.695

Gnomad SAS exome AF: 0.539

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.504 AC: 736772 AN: 1461786 Hom.: 186652 Cov.: 73 AF XY: 0.505 AC XY: 367328 AN XY: 727192

Gnomad4 AFR exome AF: 0.503

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.552

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.495

Gnomad4 OTH exome AF: 0.512

GnomAD4 genome AF: 0.508 AC: 77265 AN: 151948 Hom.: 19882 Cov.: 31 AF XY: 0.510 AC XY: 37890 AN XY: 74240

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.489

Alfa AF: 0.501 Hom.: 3531

Bravo AF: 0.503

Asia WGS AF: 0.604 AC: 2098 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia, deafness and narcolepsy Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.010
DANN	Benign	0.35

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: rs2114724; hg19: chr19-10265248; COSMIC: COSV61580166; COSMIC: COSV61580166;