rs142647321

chr19-10137146-A-C

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.4428T>G(p.His1476Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,610,694 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1476N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (14 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.01

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=0.0046668053).
• BP6: Variant 19-10137146-A-C is Benign according to our data. Variant chr19-10137146-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 196998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10137146-A-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 379 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.4428T>G	p.His1476Gln	missense_variant	37/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.4380T>G	p.His1460Gln	missense_variant	36/40
DNMT1	NM_001379.4	c.4380T>G	p.His1460Gln	missense_variant	36/40
DNMT1	NM_001318731.2	c.4065T>G	p.His1355Gln	missense_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.4428T>G	p.His1476Gln	missense_variant	37/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00245 AC: 592 AN: 241292 Hom.: 2 AF XY: 0.00242 AC XY: 318 AN XY: 131148

Gnomad AFR exome AF: 0.000794

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.0000981

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00272 AC: 3962 AN: 1458420 Hom.: 14 Cov.: 32 AF XY: 0.00267 AC XY: 1937 AN XY: 725248

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74446

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00326

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00339 Hom.: 2

Bravo AF: 0.00245

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

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	Jun 04, 2019	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 06, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DNMT1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.052
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.25
Sift	Benign	0.051	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.046	B;B
Vest4		0.15
MutPred		0.37		Gain of solvent accessibility (P = 0.0338);.;
MVP		0.80
MPC		1.1
ClinPred		0.0095	T
GERP RS		-8.8
Varity_R		0.25
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142647321; hg19: chr19-10247822;