rs62106244

Positions:

• chr19-10163444-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.892-84G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,427,718 control chromosomes in the GnomAD database, including 1,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (143 hom., cov: 31)
  • Exomes 𝑓: 0.040 (1262 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0510

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=-0.83).
• BP6: Variant 19-10163444-C-T is Benign according to our data. Variant chr19-10163444-C-T is described in ClinVar as [Benign]. Clinvar id is 670503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0341 (5197/152266) while in subpopulation NFE AF= 0.0478 (3253/68020). AF 95% confidence interval is 0.0465. There are 143 homozygotes in gnomad4. There are 2674 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5197 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.892-84G>A		intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.844-84G>A		intron_variant			NP_001305659.1
DNMT1	NM_001379.4	c.844-84G>A		intron_variant			NP_001370.1
DNMT1	NM_001318731.2	c.529-84G>A		intron_variant			NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.892-84G>A		intron_variant		1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5197 AN: 152148 Hom.: 143 Cov.: 31

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0401 AC: 51125 AN: 1275452 Hom.: 1262 AF XY: 0.0394 AC XY: 25391 AN XY: 644056

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.000104

Gnomad4 SAS exome AF: 0.00656

Gnomad4 FIN exome AF: 0.0850

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0341 AC: 5197 AN: 152266 Hom.: 143 Cov.: 31 AF XY: 0.0359 AC XY: 2674 AN XY: 74446

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.0258

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0948

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0432 Hom.: 62

Bravo AF: 0.0274

Asia WGS AF: 0.00289 AC: 10 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	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.70
DANN	Benign	0.64

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: rs62106244; hg19: chr19-10274120;