rs8101626

Positions:

• chr19-10135353-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.4773+383C>T		intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.4734+383C>T		intron_variant			NP_001305659.1
DNMT1	NM_001318731.2	c.4410+383C>T		intron_variant			NP_001305660.1
DNMT1	NM_001379.4	c.4725+383C>T		intron_variant			NP_001370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.4773+383C>T		intron_variant		1	NM_001130823.3	ENSP00000352516

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

Gnomad4 AFR exome AF: 0.748

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.547

Gnomad4 EAS exome AF: 0.756

Gnomad4 SAS exome AF: 0.675

Gnomad4 FIN exome AF: 0.589

Gnomad4 NFE exome AF: 0.557

Gnomad4 OTH exome AF: 0.590

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

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.712

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.690

Gnomad4 FIN AF: 0.623

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.649

Alfa AF: 0.590 Hom.: 33828

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs8101626; hg19: chr19-10246029;