rs2288349

Variant names:

• chr19-10146569-G-A
• rs2288349
• NM_001130823.3:c.2721-45C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.2721-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,611,166 control chromosomes in the GnomAD database, including 134,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10103 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123949 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.549

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-10146569-G-A is Benign according to our data. Variant chr19-10146569-G-A is described in ClinVar as [Benign]. Clinvar id is 681295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2721-45C>T		intron_variant	Intron 27 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2673-45C>T		intron_variant	Intron 26 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.2673-45C>T		intron_variant	Intron 26 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.2358-45C>T		intron_variant	Intron 27 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.2721-45C>T		intron_variant	Intron 27 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53433 AN: 151926 Hom.: 10104 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.361 AC: 88760 AN: 246040 Hom.: 17082 AF XY: 0.364 AC XY: 48787 AN XY: 133958

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.433

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.407 AC: 593624 AN: 1459124 Hom.: 123949 Cov.: 33 AF XY: 0.405 AC XY: 294149 AN XY: 725996

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.352 AC: 53448 AN: 152042 Hom.: 10103 Cov.: 32 AF XY: 0.346 AC XY: 25699 AN XY: 74326

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.347

Alfa AF: 0.396 Hom.: 2681

Bravo AF: 0.336

Asia WGS AF: 0.267 AC: 929 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal dominant cerebellar ataxia, deafness and narcolepsy Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2288349; hg19: chr19-10257245;