rs142903301

Positions:

• chr19-10139685-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.3939C>T​(p.Gly1313=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,040 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (11 hom., cov: 33)
  • Exomes 𝑓: 0.014 (158 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.833

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 -16 ACMG points.

• BP6: Variant 19-10139685-G-A is Benign according to our data. Variant chr19-10139685-G-A is described in ClinVar as [Benign]. Clinvar id is 257541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10139685-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00941 (1434/152344) while in subpopulation NFE AF= 0.0163 (1111/68020). AF 95% confidence interval is 0.0155. There are 11 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1434 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.3939C>T	p.Gly1313=	synonymous_variant	34/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.3891C>T	p.Gly1297=	synonymous_variant	33/40
DNMT1	NM_001379.4	c.3891C>T	p.Gly1297=	synonymous_variant	33/40
DNMT1	NM_001318731.2	c.3576C>T	p.Gly1192=	synonymous_variant	34/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.3939C>T	p.Gly1313=	synonymous_variant	34/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1435 AN: 152226 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00912 AC: 2263 AN: 248052 Hom.: 14 AF XY: 0.00921 AC XY: 1239 AN XY: 134560

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00338

Gnomad FIN exome AF: 0.00788

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.00828

GnomAD4 exome AF: 0.0136 AC: 19878 AN: 1460696 Hom.: 158 Cov.: 33 AF XY: 0.0133 AC XY: 9659 AN XY: 726650

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00323

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00376

Gnomad4 FIN exome AF: 0.00917

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.00995

GnomAD4 genome AF: 0.00941 AC: 1434 AN: 152344 Hom.: 11 Cov.: 33 AF XY: 0.00875 AC XY: 652 AN XY: 74506

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.0130 Hom.: 8

Bravo AF: 0.00881

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0150

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-0.45
CADD	Benign	15
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142903301; hg19: chr19-10250361;