rs192952800

Variant names:

• chr19-10133502-A-C
• rs192952800
• ENST00000592705.5:n.*4754T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10133502-A-C
• chr19-10133502-A-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001130823.3(DNMT1):​c.*165T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 749,132 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: DNMT1 NM_001130823.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.82
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-10133502-A-C is Benign according to our data. Variant chr19-10133502-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 327882.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.*165T>G		3_prime_UTR_variant	Exon 41 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.*165T>G		3_prime_UTR_variant	Exon 40 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.*165T>G		3_prime_UTR_variant	Exon 40 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.*165T>G		3_prime_UTR_variant	Exon 41 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.*165T>G		3_prime_UTR_variant	Exon 41 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00190 AC: 1133 AN: 596792 Hom.: 5 Cov.: 8 AF XY: 0.00187 AC XY: 584 AN XY: 312230

African (AFR) AF: 0.000130 AC: 2 AN: 15360

American (AMR) AF: 0.000943 AC: 24 AN: 25444

Ashkenazi Jewish (ASJ) AF: 0.00502 AC: 84 AN: 16724

East Asian (EAS) AF: 0.00 AC: 0 AN: 31880

South Asian (SAS) AF: 0.00110 AC: 59 AN: 53680

European-Finnish (FIN) AF: 0.000232 AC: 10 AN: 43048

Middle Eastern (MID) AF: 0.00419 AC: 10 AN: 2384

European-Non Finnish (NFE) AF: 0.00237 AC: 896 AN: 377270

Other (OTH) AF: 0.00155 AC: 48 AN: 31002

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74504

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.00105 AC: 16 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNMT1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs192952800; hg19: chr19-10244178;