19-10137594-G-T

Variant names:

• chr19-10137594-G-T
• rs10854076
• NM_001130823.3:c.4293+238C>A

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.4293+238C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• Publications: 7 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=-0.92).

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.4293+238C>A		intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.4245+238C>A		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.4245+238C>A		intron	N/A	NP_001370.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.4293+238C>A		intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.4245+238C>A		intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.*3983+238C>A		intron	N/A	ENSP00000466657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 511316 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 268894

African (AFR) AF: 0.00 AC: 0 AN: 14082

American (AMR) AF: 0.00 AC: 0 AN: 23118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14678

East Asian (EAS) AF: 0.00 AC: 0 AN: 31526

South Asian (SAS) AF: 0.00 AC: 0 AN: 48780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2154

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 318664

Other (OTH) AF: 0.00 AC: 0 AN: 28322

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.63
PhyloP100		-2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10854076; hg19: chr19-10248270;