rs4804490

Positions:

• chr19-10156335-C-A
• chr19-10156335-C-G

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.1399+56G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0948 in 1,410,962 control chromosomes in the GnomAD database, including 10,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1498 hom., cov: 31)
  • Exomes 𝑓: 0.092 (8586 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-10156335-C-A is Benign according to our data. Variant chr19-10156335-C-A is described in ClinVar as [Benign]. Clinvar id is 1251118.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.1399+56G>T		intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1351+56G>T		intron_variant			NP_001305659.1
DNMT1	NM_001318731.2	c.1036+56G>T		intron_variant			NP_001305660.1
DNMT1	NM_001379.4	c.1351+56G>T		intron_variant			NP_001370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1399+56G>T		intron_variant		1	NM_001130823.3	ENSP00000352516

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17797 AN: 151786 Hom.: 1493 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0921 AC: 115908 AN: 1259060 Hom.: 8586 AF XY: 0.0949 AC XY: 60341 AN XY: 636082

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.362

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0850

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.117 AC: 17843 AN: 151902 Hom.: 1498 Cov.: 31 AF XY: 0.123 AC XY: 9140 AN XY: 74248

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0923

Gnomad4 NFE AF: 0.0629

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0426 Hom.: 46

Bravo AF: 0.127

Asia WGS AF: 0.264 AC: 917 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	-0.80
CADD	Benign	3.2
DANN	Benign	0.53

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: rs4804490; hg19: chr19-10267011; COSMIC: COSV61579610; COSMIC: COSV61579610;