rs146694575

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-10133344-G-A
• chr19-10133344-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000586667.2(DNMT1):​n.3257C>T 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 0.00000364 in 274,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DNMT1 ENST00000586667.2 splice_region, non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000364 AC: 1 AN: 274828 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 142840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9228

American (AMR) AF: 0.00 AC: 0 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: 0.0000311 AC: 1 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: 0.00 AC: 0 AN: 164854

Other (OTH) AF: 0.00 AC: 0 AN: 16324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.4
DANN	Benign	0.77
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;