19-10133344-G-C

Variant names:

• chr19-10133344-G-C
• rs146694575
• ENST00000586667.2:n.3257C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000586667.2(DNMT1):​n.3257C>G variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 427,064 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: DNMT1 ENST00000586667.2 splice_region, non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.421
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-10133344-G-C is Benign according to our data. Variant chr19-10133344-G-C is described in ClinVar as [Benign]. Clinvar id is 369254.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.*323C>G		downstream_gene_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.*323C>G		downstream_gene_variant			NP_001305659.1
DNMT1	NM_001379.4	c.*323C>G		downstream_gene_variant			NP_001370.1
DNMT1	NM_001318731.2	c.*323C>G		downstream_gene_variant			NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.*323C>G		downstream_gene_variant		1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000306 AC: 84 AN: 274828 Hom.: 0 Cov.: 0 AF XY: 0.000280 AC XY: 40 AN XY: 142840

African (AFR) AF: 0.00748 AC: 69 AN: 9228

American (AMR) AF: 0.000542 AC: 6 AN: 11060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9522

East Asian (EAS) AF: 0.00 AC: 0 AN: 19312

South Asian (SAS) AF: 0.0000623 AC: 2 AN: 32128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1172

European-Non Finnish (NFE) AF: 0.00000607 AC: 1 AN: 164854

Other (OTH) AF: 0.000368 AC: 6 AN: 16324

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152236 Hom.: 2 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74432

African (AFR) AF: 0.00879 AC: 365 AN: 41528

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00265

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.9
DANN	Benign	0.68
PhyloP100		-0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146694575; hg19: chr19-10244020;