rs8112895

Variant names:

• chr19-10194486-A-G
• rs8112895
• NM_001130823.3:c.80+334T>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+334T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 221,016 control chromosomes in the GnomAD database, including 2,871 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 0.14 (2115 hom., cov: 32)
  • Exomes 𝑓: 0.11 (756 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 12 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.80+334T>C		intron_variant	Intron 1 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.80+334T>C		intron_variant	Intron 1 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.80+334T>C		intron_variant	Intron 1 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.-244+334T>C		intron_variant	Intron 1 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.80+334T>C		intron_variant	Intron 1 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21136 AN: 152112 Hom.: 2094 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0644

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.107 AC: 7381 AN: 68786 Hom.: 756 Cov.: 2 AF XY: 0.110 AC XY: 3878 AN XY: 35176

African (AFR) AF: 0.180 AC: 347 AN: 1932

American (AMR) AF: 0.176 AC: 237 AN: 1348

Ashkenazi Jewish (ASJ) AF: 0.0943 AC: 287 AN: 3044

East Asian (EAS) AF: 0.352 AC: 2056 AN: 5848

South Asian (SAS) AF: 0.192 AC: 1050 AN: 5480

European-Finnish (FIN) AF: 0.112 AC: 404 AN: 3600

Middle Eastern (MID) AF: 0.0559 AC: 21 AN: 376

European-Non Finnish (NFE) AF: 0.0587 AC: 2495 AN: 42492

Other (OTH) AF: 0.104 AC: 484 AN: 4666

GnomAD4 genome AF: 0.139 AC: 21215 AN: 152230 Hom.: 2115 Cov.: 32 AF XY: 0.147 AC XY: 10906 AN XY: 74430

African (AFR) AF: 0.200 AC: 8286 AN: 41532

American (AMR) AF: 0.199 AC: 3049 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3468

East Asian (EAS) AF: 0.432 AC: 2225 AN: 5152

South Asian (SAS) AF: 0.216 AC: 1044 AN: 4830

European-Finnish (FIN) AF: 0.140 AC: 1485 AN: 10618

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.0644 AC: 4384 AN: 68022

Other (OTH) AF: 0.127 AC: 267 AN: 2108

Alfa AF: 0.0963 Hom.: 171

Bravo AF: 0.147

Asia WGS AF: 0.322 AC: 1118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.4
DANN	Benign	0.51
PhyloP100		0.20
PromoterAI		0.031	Neutral
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: rs8112895; hg19: chr19-10305162;