rs10407514

Variant names:

• chr19-10144436-C-G
• rs10407514
• NM_001130823.3:c.2895-449G>C

Variant summary

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

The NM_001130823.3(DNMT1):​c.2895-449G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 250,436 control chromosomes in the GnomAD database, including 3,170 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 0.14 (2187 hom., cov: 31)
  • Exomes 𝑓: 0.098 (983 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57
• Publications: 4 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.2895-449G>C		intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.2847-449G>C		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.2847-449G>C		intron	N/A	NP_001370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.2895-449G>C		intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.2847-449G>C		intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.*2585-449G>C		intron	N/A	ENSP00000466657.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21530 AN: 151724 Hom.: 2167 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0643

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0980 AC: 9666 AN: 98594 Hom.: 983 Cov.: 0 AF XY: 0.105 AC XY: 5461 AN XY: 51776

African (AFR) AF: 0.169 AC: 494 AN: 2916

American (AMR) AF: 0.199 AC: 854 AN: 4284

Ashkenazi Jewish (ASJ) AF: 0.0800 AC: 195 AN: 2436

East Asian (EAS) AF: 0.414 AC: 1760 AN: 4256

South Asian (SAS) AF: 0.166 AC: 2531 AN: 15240

European-Finnish (FIN) AF: 0.0948 AC: 411 AN: 4334

Middle Eastern (MID) AF: 0.0820 AC: 30 AN: 366

European-Non Finnish (NFE) AF: 0.0498 AC: 2978 AN: 59788

Other (OTH) AF: 0.0830 AC: 413 AN: 4974

GnomAD4 genome AF: 0.142 AC: 21610 AN: 151842 Hom.: 2187 Cov.: 31 AF XY: 0.149 AC XY: 11083 AN XY: 74192

African (AFR) AF: 0.210 AC: 8695 AN: 41416

American (AMR) AF: 0.202 AC: 3082 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2206 AN: 5154

South Asian (SAS) AF: 0.216 AC: 1040 AN: 4816

European-Finnish (FIN) AF: 0.140 AC: 1474 AN: 10520

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0644 AC: 4371 AN: 67922

Other (OTH) AF: 0.128 AC: 270 AN: 2104

Alfa AF: 0.0957 Hom.: 135

Bravo AF: 0.150

Asia WGS AF: 0.311 AC: 1077 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.38
DANN	Benign	0.38
PhyloP100		-1.6
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: rs10407514; hg19: chr19-10255112;