rs11085721

Variant names:

• chr19-10207300-G-C
• rs11085721
• ENST00000588952.5:c.-284+11452C>G

Variant summary

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

The ENST00000592342.5(DNMT1):​c.-284+23904C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,130 control chromosomes in the GnomAD database, including 1,528 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 (1528 hom., cov: 32)
• Consequence: DNMT1 ENST00000592342.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 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+11452C>G		intron_variant	Intron 2 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-284+23904C>G		intron_variant	Intron 1 of 6	3		ENSP00000465993.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20336 AN: 152012 Hom.: 1532 Cov.: 32

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.173

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

GnomAD4 genome AF: 0.134 AC: 20321 AN: 152130 Hom.: 1528 Cov.: 32 AF XY: 0.131 AC XY: 9775 AN XY: 74372

African (AFR) AF: 0.0840 AC: 3488 AN: 41516

American (AMR) AF: 0.131 AC: 1997 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1048 AN: 5158

South Asian (SAS) AF: 0.183 AC: 882 AN: 4824

European-Finnish (FIN) AF: 0.0933 AC: 989 AN: 10600

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10934 AN: 67982

Other (OTH) AF: 0.171 AC: 362 AN: 2114

Alfa AF: 0.138 Hom.: 196

Bravo AF: 0.138

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.57
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs11085721; hg19: chr19-10317976;