19-10199716-A-G

Variant names:

• chr19-10199716-A-G
• rs2116940
• ENST00000588118.5:c.10+1158T>C

Variant summary

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

The ENST00000592342.5(DNMT1):​c.-283-17639T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,084 control chromosomes in the GnomAD database, including 1,909 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 0.13 (1909 hom., cov: 31)
• Consequence: DNMT1 ENST00000592342.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 17 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000592342.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000588118.5	TSL:5	c.10+1158T>C		intron	N/A	ENSP00000465223.1	K7EJL0
	DNMT1	ENST00000588952.5	TSL:5	c.-283-17639T>C		intron	N/A	ENSP00000467050.1	K7ENQ6
	DNMT1	ENST00000592342.5	TSL:3	c.-283-17639T>C		intron	N/A	ENSP00000465993.1	K7ELB1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19907 AN: 151966 Hom.: 1889 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.131 AC: 19987 AN: 152084 Hom.: 1909 Cov.: 31 AF XY: 0.137 AC XY: 10156 AN XY: 74362

African (AFR) AF: 0.191 AC: 7935 AN: 41472

American (AMR) AF: 0.195 AC: 2976 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2081 AN: 5182

South Asian (SAS) AF: 0.208 AC: 1005 AN: 4824

European-Finnish (FIN) AF: 0.0925 AC: 980 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0630 AC: 4283 AN: 67994

Other (OTH) AF: 0.120 AC: 254 AN: 2108

Alfa AF: 0.0925 Hom.: 2148

Bravo AF: 0.143

Asia WGS AF: 0.275 AC: 957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.058
DANN	Benign	0.62
PhyloP100		-0.023

Splicing

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

Other links and lift over

dbSNP: rs2116940; hg19: chr19-10310392;