rs74505694

Positions:

• chr19-10149661-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.2382-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,613,518 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (113 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005348
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0740

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=-0.77).
• BP6: Variant 19-10149661-G-A is Benign according to our data. Variant chr19-10149661-G-A is described in ClinVar as [Benign]. Clinvar id is 327902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10149661-G-A is described in Lovd as [Likely_benign]. Variant chr19-10149661-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00579 (882/152304) while in subpopulation EAS AF= 0.0334 (173/5174). AF 95% confidence interval is 0.0294. There are 18 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 882 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.2382-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359526.9
DNMT1	NM_001318730.2	c.2334-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DNMT1	NM_001318731.2	c.2019-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DNMT1	NM_001379.4	c.2334-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.2382-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152186 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0334

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00872 AC: 2186 AN: 250756 Hom.: 40 AF XY: 0.00855 AC XY: 1159 AN XY: 135602

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0328

Gnomad SAS exome AF: 0.00925

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00387 AC: 5651 AN: 1461214 Hom.: 113 Cov.: 32 AF XY: 0.00392 AC XY: 2853 AN XY: 726896

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0354

Gnomad4 SAS exome AF: 0.00855

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.000603

Gnomad4 OTH exome AF: 0.00756

GnomAD4 genome AF: 0.00579 AC: 882 AN: 152304 Hom.: 18 Cov.: 32 AF XY: 0.00786 AC XY: 585 AN XY: 74474

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0473

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00193

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2020	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2016	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. -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
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. -

DNMT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.014
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: rs74505694; hg19: chr19-10260337;