19-10180797-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001130823.3(DNMT1):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,950 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (9 hom., cov: 31)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.392

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNMT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023405552).
• BP6: Variant 19-10180797-C-T is Benign according to our data. Variant chr19-10180797-C-T is described in ClinVar as [Benign]. Clinvar id is 137132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180797-C-T is described in Lovd as [Benign]. Variant chr19-10180797-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 1423 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.206G>A	p.Arg69His	missense_variant	3/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.206G>A	p.Arg69His	missense_variant	3/40
DNMT1	NM_001379.4	c.206G>A	p.Arg69His	missense_variant	3/40
DNMT1	NM_001318731.2	c.-118G>A		5_prime_UTR_variant	3/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.206G>A	p.Arg69His	missense_variant	3/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.00936 AC: 1423 AN: 152102 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0101 AC: 2549 AN: 251240 Hom.: 19 AF XY: 0.0101 AC XY: 1377 AN XY: 135820

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0113 AC: 16539 AN: 1461730 Hom.: 113 Cov.: 31 AF XY: 0.0111 AC XY: 8049 AN XY: 727186

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.00935 AC: 1424 AN: 152220 Hom.: 9 Cov.: 31 AF XY: 0.00956 AC XY: 712 AN XY: 74442

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0109 Hom.: 20

Bravo AF: 0.00700

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00908 AC: 1102

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNMT1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Benign	0.58
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N;N;.
REVEL	Benign	0.040
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.11
MPC		0.51
ClinPred		0.0085	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.046

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: rs61750053; hg19: chr19-10291473; COSMIC: COSV61577141; COSMIC: COSV61577141;