rs10420321

Variant names:

• chr19-10189741-A-G
• rs10420321
• NM_001130823.3:c.80+5079T>C

Variant summary

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

The NM_001130823.3(DNMT1):​c.80+5079T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 151,956 control chromosomes in the GnomAD database, including 1,504 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 0.12 (1504 hom., cov: 31)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. 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
	DNMT1	NM_001130823.3	MANE Select	c.80+5079T>C		intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.80+5079T>C		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.80+5079T>C		intron	N/A	NP_001370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.80+5079T>C		intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.80+5079T>C		intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.80+5079T>C		intron	N/A	ENSP00000466657.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17802 AN: 151838 Hom.: 1499 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0926

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.117 AC: 17850 AN: 151956 Hom.: 1504 Cov.: 31 AF XY: 0.123 AC XY: 9129 AN XY: 74264

African (AFR) AF: 0.144 AC: 5951 AN: 41454

American (AMR) AF: 0.189 AC: 2877 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2060 AN: 5160

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4818

European-Finnish (FIN) AF: 0.0926 AC: 979 AN: 10570

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0628 AC: 4268 AN: 67954

Other (OTH) AF: 0.112 AC: 237 AN: 2110

Alfa AF: 0.0841 Hom.: 101

Bravo AF: 0.127

Asia WGS AF: 0.264 AC: 920 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.51
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10420321; hg19: chr19-10300417;