rs4804494

Positions:

• chr19-10192773-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130823.3(DNMT1):​c.80+2047A>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 151,888 control chromosomes in the GnomAD database, including 1,498 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 (1498 hom., cov: 31)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.80+2047A>C		intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.80+2047A>C		intron_variant			NP_001305659.1
DNMT1	NM_001318731.2	c.-244+2047A>C		intron_variant			NP_001305660.1
DNMT1	NM_001379.4	c.80+2047A>C		intron_variant			NP_001370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.80+2047A>C		intron_variant		1	NM_001130823.3	ENSP00000352516

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17788 AN: 151770 Hom.: 1493 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: 0.398

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0627

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: 17836 AN: 151888 Hom.: 1498 Cov.: 31 AF XY: 0.123 AC XY: 9127 AN XY: 74226

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.0928

Gnomad4 NFE AF: 0.0628

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0826 Hom.: 119

Bravo AF: 0.127

Asia WGS AF: 0.264 AC: 919 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.73

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: rs4804494; hg19: chr19-10303449;