chr19-10162679-G-A

Position:

• chr19-10162679-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130823.3(DNMT1):​c.996C>T​(p.Asp332Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,611,458 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (78 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.194

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-10162679-G-A is Benign according to our data. Variant chr19-10162679-G-A is described in ClinVar as [Benign]. Clinvar id is 327917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10162679-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.996C>T	p.Asp332Asp	synonymous_variant	13/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.948C>T	p.Asp316Asp	synonymous_variant	12/40		NP_001305659.1
DNMT1	NM_001379.4	c.948C>T	p.Asp316Asp	synonymous_variant	12/40		NP_001370.1
DNMT1	NM_001318731.2	c.633C>T	p.Asp211Asp	synonymous_variant	13/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.996C>T	p.Asp332Asp	synonymous_variant	13/41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 416 AN: 150566 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000501

Gnomad OTH AF: 0.00339

GnomAD3 exomes AF: 0.00625 AC: 1570 AN: 251268 Hom.: 44 AF XY: 0.00583 AC XY: 792 AN XY: 135822

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.0691

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00636

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00236 AC: 3454 AN: 1460820 Hom.: 78 Cov.: 34 AF XY: 0.00238 AC XY: 1729 AN XY: 726762

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.0598

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00674

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00275 AC: 415 AN: 150638 Hom.: 9 Cov.: 31 AF XY: 0.00343 AC XY: 252 AN XY: 73436

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.000529

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0548

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.000501

Gnomad4 OTH AF: 0.00336

Alfa AF: 0.00127 Hom.: 2

Bravo AF: 0.00346

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.2
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs16999358; hg19: chr19-10273355;