rs16999593

Positions:

• chr19-10180505-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.290A>G​(p.His97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 1,614,168 control chromosomes in the GnomAD database, including 1,034 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. H97Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (142 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (892 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0510

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNMT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013153255).
• BP6: Variant 19-10180505-T-C is Benign according to our data. Variant chr19-10180505-T-C is described in ClinVar as [Benign]. Clinvar id is 257539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180505-T-C is described in Lovd as [Benign]. Variant chr19-10180505-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.290A>G	p.His97Arg	missense_variant	4/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.290A>G	p.His97Arg	missense_variant	4/40
DNMT1	NM_001379.4	c.290A>G	p.His97Arg	missense_variant	4/40
DNMT1	NM_001318731.2	c.-74A>G		5_prime_UTR_variant	4/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.290A>G	p.His97Arg	missense_variant	4/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1818 AN: 152156 Hom.: 141 Cov.: 31

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0245 AC: 6155 AN: 251494 Hom.: 509 AF XY: 0.0211 AC XY: 2872 AN XY: 135922

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.211

Gnomad SAS exome AF: 0.00480

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00786 AC: 11484 AN: 1461894 Hom.: 892 Cov.: 31 AF XY: 0.00755 AC XY: 5490 AN XY: 727248

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.00523

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0120 AC: 1822 AN: 152274 Hom.: 142 Cov.: 31 AF XY: 0.0130 AC XY: 966 AN XY: 74450

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0397

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00673 Hom.: 172

Bravo AF: 0.0160

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0217 AC: 2637

Asia WGS AF: 0.0780 AC: 272 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely 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	Athena Diagnostics	Aug 30, 2018	- -
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	GeneDx	Mar 03, 2015	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -

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	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.82
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N;.
REVEL	Benign	0.021
Sift	Benign	0.88	T;T;.
Sift4G	Benign	0.72	T;T;T
Polyphen		0.49	P;B;.
Vest4		0.27
MPC		1.0
ClinPred		0.0067	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs16999593; hg19: chr19-10291181; COSMIC: COSV61577559; COSMIC: COSV61577559;