rs62106244

Variant names:

• chr19-10163444-C-T
• rs62106244
• NM_001130823.3:c.892-84G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant cerebellar ataxia, deafness and narcolepsy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5197 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.892-84G>A		intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.844-84G>A		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.844-84G>A		intron	N/A	NP_001370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.892-84G>A		intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.844-84G>A		intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000591764.1	TSL:1	n.70-84G>A		intron	N/A

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

African (AFR) AF: 0.00618 AC: 183 AN: 29630

American (AMR) AF: 0.0198 AC: 874 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 511 AN: 24950

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38572

South Asian (SAS) AF: 0.00656 AC: 540 AN: 82310

European-Finnish (FIN) AF: 0.0850 AC: 4335 AN: 51026

Middle Eastern (MID) AF: 0.0164 AC: 89 AN: 5430

European-Non Finnish (NFE) AF: 0.0451 AC: 42653 AN: 945178

Other (OTH) AF: 0.0358 AC: 1936 AN: 54110

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

African (AFR) AF: 0.00782 AC: 325 AN: 41568

American (AMR) AF: 0.0258 AC: 394 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4826

European-Finnish (FIN) AF: 0.0948 AC: 1004 AN: 10588

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3253 AN: 68020

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0442 Hom.: 254

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

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.70
DANN	Benign	0.64
PhyloP100		-0.051
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62106244; hg19: chr19-10274120;