rs2162560

Variant names:

• chr19-10168778-G-A
• rs2162560
• NM_001130823.3:c.769-414C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130823.3(DNMT1):​c.769-414C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 151,994 control chromosomes in the GnomAD database, including 10,048 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10048 hom., cov: 32)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.262
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.769-414C>T		intron_variant	Intron 9 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.721-414C>T		intron_variant	Intron 8 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.721-414C>T		intron_variant	Intron 8 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.406-414C>T		intron_variant	Intron 9 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.769-414C>T		intron_variant	Intron 9 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53333 AN: 151876 Hom.: 10049 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.345

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.351 AC: 53345 AN: 151994 Hom.: 10048 Cov.: 32 AF XY: 0.346 AC XY: 25691 AN XY: 74296

African (AFR) AF: 0.241 AC: 9978 AN: 41460

American (AMR) AF: 0.286 AC: 4359 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3468

East Asian (EAS) AF: 0.239 AC: 1237 AN: 5166

South Asian (SAS) AF: 0.330 AC: 1592 AN: 4822

European-Finnish (FIN) AF: 0.375 AC: 3960 AN: 10548

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29375 AN: 67956

Other (OTH) AF: 0.349 AC: 738 AN: 2112

Alfa AF: 0.403 Hom.: 12007

Bravo AF: 0.335

Asia WGS AF: 0.279 AC: 970 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.26
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: rs2162560; hg19: chr19-10279454;