rs8106605

Variant names:

• chr19-10212956-T-G
• rs8106605
• ENST00000588952.5:c.-284+5796A>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+5796A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,126 control chromosomes in the GnomAD database, including 2,039 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 0.16 (2039 hom., cov: 31)
• Consequence: DNMT1 ENST00000588952.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 0 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000588952.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000588952.5	TSL:5	c.-284+5796A>C		intron	N/A	ENSP00000467050.1
	DNMT1	ENST00000592342.5	TSL:3	c.-284+18248A>C		intron	N/A	ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24294 AN: 152008 Hom.: 2043 Cov.: 31

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.160 AC: 24284 AN: 152126 Hom.: 2039 Cov.: 31 AF XY: 0.156 AC XY: 11621 AN XY: 74390

African (AFR) AF: 0.192 AC: 7977 AN: 41502

American (AMR) AF: 0.134 AC: 2048 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1042 AN: 5172

South Asian (SAS) AF: 0.173 AC: 836 AN: 4822

European-Finnish (FIN) AF: 0.0904 AC: 957 AN: 10590

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10465 AN: 67978

Other (OTH) AF: 0.177 AC: 374 AN: 2108

Alfa AF: 0.160 Hom.: 572

Bravo AF: 0.166

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.0
DANN	Benign	0.52
PhyloP100		0.011

Splicing

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

Other links and lift over

dbSNP: rs8106605; hg19: chr19-10323632;