19-10139685-G-A

Position:

chr19-10139685-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.833

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
DNMT1	NM_001130823.3 linkuse as main transcript	c.3939C>T	p.Gly1313=	synonymous_variant	34/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2 linkuse as main transcript	c.3891C>T	p.Gly1297=	synonymous_variant	33/40		NP_001305659.1
DNMT1	NM_001379.4 linkuse as main transcript	c.3891C>T	p.Gly1297=	synonymous_variant	33/40		NP_001370.1
DNMT1	NM_001318731.2 linkuse as main transcript	c.3576C>T	p.Gly1192=	synonymous_variant	34/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 linkuse as main transcript	c.3939C>T	p.Gly1313=	synonymous_variant	34/41	1	NM_001130823.3	ENSP00000352516		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1435

AN:

152226

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00921

AC XY:

1239

AN XY:

134560

show subpopulations

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.:

AF XY:

0.0133

AC XY:

9659

AN XY:

726650

show subpopulations

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.:

Cov.:

AF XY:

0.00875

AC XY:

652

AN XY:

74506

show subpopulations

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.:

Bravo

AF:

0.00881

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0145

EpiControl

AF:

0.0150

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2018	- -

not specified

Benign:3

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

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over