19-10176959-A-T

Variant names:

• chr19-10176959-A-T
• rs6511685
• NM_001130823.3:c.569+333T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001130823.3(DNMT1):​c.569+333T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,916 control chromosomes in the GnomAD database, including 20,156 homozygotes. 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: 𝑓 0.51 (20156 hom., cov: 31)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.820
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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.569+333T>A		intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.521+333T>A		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.521+333T>A		intron	N/A	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.569+333T>A		intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.521+333T>A		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*259+333T>A		intron	N/A	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77727 AN: 151798 Hom.: 20123 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77824 AN: 151916 Hom.: 20156 Cov.: 31 AF XY: 0.514 AC XY: 38116 AN XY: 74214

African (AFR) AF: 0.515 AC: 21349 AN: 41458

American (AMR) AF: 0.493 AC: 7511 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1928 AN: 3466

East Asian (EAS) AF: 0.675 AC: 3488 AN: 5166

South Asian (SAS) AF: 0.547 AC: 2633 AN: 4814

European-Finnish (FIN) AF: 0.515 AC: 5424 AN: 10530

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33787 AN: 67948

Other (OTH) AF: 0.492 AC: 1038 AN: 2108

Alfa AF: 0.491 Hom.: 2189

Bravo AF: 0.507

Asia WGS AF: 0.606 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.7
DANN	Benign	0.84
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs6511685; hg19: chr19-10287635;