rs12984523

Variant names:

• chr19-10196143-C-T
• rs12984523
• ENST00000588118.5:c.11-1089G>A

Variant summary

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

The ENST00000588118.5(DNMT1):​c.11-1089G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 152,036 control chromosomes in the GnomAD database, including 18,303 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 0.49 (18303 hom., cov: 32)
• Consequence: DNMT1 ENST00000588118.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.422
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.498 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	ENST00000588118.5	c.11-1089G>A		intron_variant	Intron 2 of 7	5		ENSP00000465223.1
DNMT1	ENST00000588952.5	c.-283-14066G>A		intron_variant	Intron 2 of 8	5		ENSP00000467050.1
DNMT1	ENST00000592342.5	c.-283-14066G>A		intron_variant	Intron 1 of 6	3		ENSP00000465993.1
DNMT1	ENST00000586800.5	c.-284+4731G>A		intron_variant	Intron 2 of 4	3		ENSP00000465555.1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74106 AN: 151918 Hom.: 18308 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.513

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

GnomAD4 genome AF: 0.488 AC: 74127 AN: 152036 Hom.: 18303 Cov.: 32 AF XY: 0.486 AC XY: 36140 AN XY: 74328

African (AFR) AF: 0.485 AC: 20120 AN: 41480

American (AMR) AF: 0.506 AC: 7728 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1541 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1674 AN: 5170

South Asian (SAS) AF: 0.452 AC: 2183 AN: 4830

European-Finnish (FIN) AF: 0.484 AC: 5114 AN: 10572

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.503 AC: 34155 AN: 67940

Other (OTH) AF: 0.509 AC: 1075 AN: 2114

Alfa AF: 0.500 Hom.: 2346

Bravo AF: 0.493

Asia WGS AF: 0.392 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.63
PhyloP100		0.42

Splicing

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

Other links and lift over

dbSNP: rs12984523; hg19: chr19-10306819;