rs146112081

Positions:

• chr19-10180853-G-A
• chr19-10180853-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001130823.3(DNMT1):​c.150C>T​(p.His50=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,042 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.358

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-10180853-G-A is Benign according to our data. Variant chr19-10180853-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196315.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=3}. Variant chr19-10180853-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.358 with no splicing effect.
• BS2: High AC in GnomAd4 at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.150C>T	p.His50=	synonymous_variant	3/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.150C>T	p.His50=	synonymous_variant	3/40
DNMT1	NM_001379.4	c.150C>T	p.His50=	synonymous_variant	3/40
DNMT1	NM_001318731.2	c.-174C>T		5_prime_UTR_variant	3/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.150C>T	p.His50=	synonymous_variant	3/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152088 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00136 AC: 341 AN: 251216 Hom.: 0 AF XY: 0.00139 AC XY: 189 AN XY: 135798

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00199 AC: 2914 AN: 1461836 Hom.: 6 Cov.: 30 AF XY: 0.00202 AC XY: 1471 AN XY: 727226

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152206 Hom.: 0 Cov.: 31 AF XY: 0.00165 AC XY: 123 AN XY: 74428

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00167

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	May 01, 2024	DNMT1: BP4, BP7 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs146112081; hg19: chr19-10291529;