rs16999714

Variant names:

• chr19-10205774-A-G
• rs16999714
• ENST00000588952.5:c.-284+12978T>C

Variant summary

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

The ENST00000588952.5(DNMT1):​c.-284+12978T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,046 control chromosomes in the GnomAD database, including 1,657 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 0.14 (1657 hom., cov: 32)
• Consequence: DNMT1 ENST00000588952.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 9 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 (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000588952.5	c.-284+12978T>C		intron_variant	Intron 2 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-283-23697T>C		intron_variant	Intron 1 of 6	3		ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21440 AN: 151928 Hom.: 1662 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.141 AC: 21424 AN: 152046 Hom.: 1657 Cov.: 32 AF XY: 0.138 AC XY: 10267 AN XY: 74310

African (AFR) AF: 0.102 AC: 4222 AN: 41502

American (AMR) AF: 0.133 AC: 2037 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 498 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1063 AN: 5154

South Asian (SAS) AF: 0.188 AC: 904 AN: 4808

European-Finnish (FIN) AF: 0.0935 AC: 990 AN: 10590

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.165 AC: 11187 AN: 67940

Other (OTH) AF: 0.176 AC: 371 AN: 2112

Alfa AF: 0.158 Hom.: 4429

Bravo AF: 0.145

Asia WGS AF: 0.193 AC: 674 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	2.4
DANN	Benign	0.38
PhyloP100		-0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16999714; hg19: chr19-10316450;