19-10164984-C-T

Variant names:

• chr19-10164984-C-T
• rs8101866
• NM_001130823.3:c.891+1614G>A

Variant summary

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

The NM_001130823.3(DNMT1):​c.891+1614G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 140,312 control chromosomes in the GnomAD database, including 18,914 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 0.52 (18914 hom., cov: 21)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 14 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.891+1614G>A		intron_variant	Intron 11 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.843+1614G>A		intron_variant	Intron 10 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.843+1614G>A		intron_variant	Intron 10 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.528+1614G>A		intron_variant	Intron 11 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.891+1614G>A		intron_variant	Intron 11 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.524 AC: 73457 AN: 140200 Hom.: 18886 Cov.: 21

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.581

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.501

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

GnomAD4 genome AF: 0.524 AC: 73543 AN: 140312 Hom.: 18914 Cov.: 21 AF XY: 0.529 AC XY: 35656 AN XY: 67446

African (AFR) AF: 0.523 AC: 19529 AN: 37310

American (AMR) AF: 0.511 AC: 6706 AN: 13114

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1896 AN: 3410

East Asian (EAS) AF: 0.693 AC: 3292 AN: 4752

South Asian (SAS) AF: 0.575 AC: 2492 AN: 4332

European-Finnish (FIN) AF: 0.563 AC: 4739 AN: 8420

Middle Eastern (MID) AF: 0.565 AC: 156 AN: 276

European-Non Finnish (NFE) AF: 0.505 AC: 33256 AN: 65884

Other (OTH) AF: 0.505 AC: 981 AN: 1942

Alfa AF: 0.368 Hom.: 1110

Bravo AF: 0.503

Asia WGS AF: 0.600 AC: 2081 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.58
DANN	Benign	0.28
PhyloP100		-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: rs8101866; hg19: chr19-10275660;