19-10154783-G-T

Position:

• chr19-10154783-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000359526.9(DNMT1):​c.1645-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DNMT1 ENST00000359526.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008077
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0700

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1645-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1597-10C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001305659.1
DNMT1	NM_001318731.2	c.1282-10C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001305660.1
DNMT1	NM_001379.4	c.1597-10C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1645-10C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130823.3	ENSP00000352516

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251404 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461874 Hom.: 0 Cov.: 37 AF XY: 0.0000316 AC XY: 23 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2019

This variant has not been reported in the literature in individuals with DNMT1-related disease. This variant is present in population databases (rs752563425, ExAC 0.001%). This sequence change falls in intron 20 of the DNMT1 gene. It does not directly change the encoded amino acid sequence of the DNMT1 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.34
BranchPoint Hunter		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs752563425; hg19: chr19-10265459;