rs2288349

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant cerebellar ataxia, deafness and narcolepsy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.2721-45C>T		intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.2673-45C>T		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.2673-45C>T		intron	N/A	NP_001370.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.2721-45C>T		intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.2673-45C>T		intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.*2411-45C>T		intron	N/A	ENSP00000466657.1

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

GnomAD2 exomes AF: 0.361 AC: 88760 AN: 246040 AF XY: 0.364

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 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

African (AFR) AF: 0.240 AC: 8016 AN: 33462

American (AMR) AF: 0.245 AC: 10935 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11503 AN: 26126

East Asian (EAS) AF: 0.222 AC: 8805 AN: 39682

South Asian (SAS) AF: 0.315 AC: 27112 AN: 86148

European-Finnish (FIN) AF: 0.396 AC: 20487 AN: 51788

Middle Eastern (MID) AF: 0.471 AC: 2704 AN: 5742

European-Non Finnish (NFE) AF: 0.433 AC: 480733 AN: 1111212

Other (OTH) AF: 0.387 AC: 23329 AN: 60314

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

African (AFR) AF: 0.243 AC: 10070 AN: 41482

American (AMR) AF: 0.286 AC: 4371 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1543 AN: 3468

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5174

South Asian (SAS) AF: 0.309 AC: 1488 AN: 4816

European-Finnish (FIN) AF: 0.377 AC: 3985 AN: 10572

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29449 AN: 67956

Other (OTH) AF: 0.347 AC: 732 AN: 2112

Alfa AF: 0.393 Hom.: 2712

Bravo AF: 0.336

Asia WGS AF: 0.267 AC: 929 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant cerebellar ataxia, deafness and narcolepsy (1)
-	-	1	Hereditary sensory neuropathy-deafness-dementia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.58
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288349; hg19: chr19-10257245; COSMIC: COSV107430335; COSMIC: COSV107430335;