rs8101626

Variant names:

• chr19-10135353-G-A
• rs8101626
• NM_001130823.3:c.4773+383C>T

Variant summary

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

The NM_001130823.3(DNMT1):​c.4773+383C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 296,412 control chromosomes in the GnomAD database, including 59,688 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 0.65 (32343 hom., cov: 30)
  • Exomes 𝑓: 0.61 (27345 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.293
• Publications: 9 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.4773+383C>T		intron_variant	Intron 39 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.4734+383C>T		intron_variant	Intron 38 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.4725+383C>T		intron_variant	Intron 38 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.4410+383C>T		intron_variant	Intron 39 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.4773+383C>T		intron_variant	Intron 39 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98003 AN: 151734 Hom.: 32302 Cov.: 30

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.653

GnomAD4 exome AF: 0.606 AC: 87584 AN: 144560 Hom.: 27345 AF XY: 0.612 AC XY: 46947 AN XY: 76660

African (AFR) AF: 0.748 AC: 3664 AN: 4900

American (AMR) AF: 0.732 AC: 5559 AN: 7594

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 2065 AN: 3774

East Asian (EAS) AF: 0.756 AC: 6010 AN: 7952

South Asian (SAS) AF: 0.675 AC: 16121 AN: 23900

European-Finnish (FIN) AF: 0.589 AC: 4053 AN: 6882

Middle Eastern (MID) AF: 0.530 AC: 287 AN: 542

European-Non Finnish (NFE) AF: 0.557 AC: 45350 AN: 81426

Other (OTH) AF: 0.590 AC: 4475 AN: 7590

GnomAD4 genome AF: 0.646 AC: 98104 AN: 151852 Hom.: 32343 Cov.: 30 AF XY: 0.652 AC XY: 48373 AN XY: 74196

African (AFR) AF: 0.752 AC: 31135 AN: 41412

American (AMR) AF: 0.712 AC: 10877 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1917 AN: 3472

East Asian (EAS) AF: 0.755 AC: 3899 AN: 5164

South Asian (SAS) AF: 0.690 AC: 3312 AN: 4800

European-Finnish (FIN) AF: 0.623 AC: 6561 AN: 10530

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.566 AC: 38404 AN: 67904

Other (OTH) AF: 0.649 AC: 1365 AN: 2102

Alfa AF: 0.604 Hom.: 66317

Bravo AF: 0.661

Asia WGS AF: 0.731 AC: 2542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.38
PhyloP100		0.29
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: rs8101626; hg19: chr19-10246029;