ENST00000917926.1:c.*323C>T

Variant names:

• chr19-10133344-G-A
• rs146694575
• ENST00000917926.1:c.*323C>T

Variant summary

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

The ENST00000917926.1(DNMT1):​c.*323C>T variant causes a splice region 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 ENST00000917926.1 splice_region
• 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: 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: 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000917926.1. 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.*323C>T		downstream_gene	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.*323C>T		downstream_gene	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.*323C>T		downstream_gene	N/A	NP_001370.1	P26358-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000917926.1		c.*323C>T		splice_region	Exon 41 of 41	ENSP00000587985.1
	DNMT1	ENST00000917926.1		c.*323C>T		3_prime_UTR	Exon 41 of 41	ENSP00000587985.1
	DNMT1	ENST00000586667.2	TSL:2	n.3257C>T		splice_region non_coding_transcript_exon	Exon 18 of 18

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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;