rs759920

Variant names:

• chr19-10174102-A-G
• rs759920
• NM_001130823.3:c.649-197T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10174102-A-G
• chr19-10174102-A-C
• chr19-10174102-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.649-197T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,940 control chromosomes in the GnomAD database, including 20,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.51 (20149 hom., cov: 31)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.691
• Publications: 18 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-10174102-A-G is Benign according to our data. Variant chr19-10174102-A-G is described in ClinVar as Benign. ClinVar VariationId is 679318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.649-197T>C		intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.601-197T>C		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.601-197T>C		intron	N/A	NP_001370.1	P26358-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.649-197T>C		intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.601-197T>C		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*339-197T>C		intron	N/A	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77691 AN: 151822 Hom.: 20116 Cov.: 31

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77788 AN: 151940 Hom.: 20149 Cov.: 31 AF XY: 0.513 AC XY: 38107 AN XY: 74264

African (AFR) AF: 0.515 AC: 21332 AN: 41402

American (AMR) AF: 0.491 AC: 7472 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1921 AN: 3468

East Asian (EAS) AF: 0.674 AC: 3483 AN: 5164

South Asian (SAS) AF: 0.547 AC: 2642 AN: 4830

European-Finnish (FIN) AF: 0.516 AC: 5453 AN: 10560

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33781 AN: 67970

Other (OTH) AF: 0.492 AC: 1038 AN: 2110

Alfa AF: 0.406 Hom.: 1568

Bravo AF: 0.506

Asia WGS AF: 0.606 AC: 2105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.69
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: rs759920; hg19: chr19-10284778; COSMIC: COSV61584146; COSMIC: COSV61584146;