chr19-10133541-T-A

Variant names:

• chr19-10133541-T-A
• rs886054126
• NM_001130823.3:c.*126A>T

Variant summary

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

The NM_001130823.3(DNMT1):​c.*126A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 951,644 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: 0.0000011 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Genomics England PanelApp
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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=-0.76).

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.*126A>T		3_prime_UTR	Exon 41 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.*126A>T		3_prime_UTR	Exon 40 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.*126A>T		3_prime_UTR	Exon 40 of 40	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.*126A>T		3_prime_UTR	Exon 41 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.*126A>T		3_prime_UTR	Exon 40 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*4715A>T		non_coding_transcript_exon	Exon 41 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 951644 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 483044

African (AFR) AF: 0.00 AC: 0 AN: 22674

American (AMR) AF: 0.00 AC: 0 AN: 33986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21804

East Asian (EAS) AF: 0.00 AC: 0 AN: 33398

South Asian (SAS) AF: 0.00 AC: 0 AN: 69186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3308

European-Non Finnish (NFE) AF: 0.00000148 AC: 1 AN: 676280

Other (OTH) AF: 0.00 AC: 0 AN: 42912

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.4
DANN	Benign	0.77
PhyloP100		0.078
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886054126; hg19: chr19-10244217;