rs10423341

Positions:

• chr19-10156590-C-A
• chr19-10156590-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.1281-81G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 981,090 control chromosomes in the GnomAD database, including 9,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1890 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7343 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.651

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-10156590-C-A is Benign according to our data. Variant chr19-10156590-C-A is described in ClinVar as [Benign]. Clinvar id is 1272273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1281-81G>T		intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1233-81G>T		intron_variant			NP_001305659.1
DNMT1	NM_001379.4	c.1233-81G>T		intron_variant			NP_001370.1
DNMT1	NM_001318731.2	c.918-81G>T		intron_variant			NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1281-81G>T		intron_variant		1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19892 AN: 152016 Hom.: 1870 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.103 AC: 85478 AN: 828956 Hom.: 7343 AF XY: 0.106 AC XY: 46250 AN XY: 437384

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0857

Gnomad4 NFE exome AF: 0.0604

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.131 AC: 19971 AN: 152134 Hom.: 1890 Cov.: 32 AF XY: 0.137 AC XY: 10160 AN XY: 74368

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.0925

Gnomad4 NFE AF: 0.0629

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0884 Hom.: 115

Bravo AF: 0.142

Asia WGS AF: 0.273 AC: 948 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.23
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10423341; hg19: chr19-10267266; COSMIC: COSV61584710; COSMIC: COSV61584710;