rs10407514

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2895-449G>C		intron_variant	Intron 28 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2847-449G>C		intron_variant	Intron 27 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.2847-449G>C		intron_variant	Intron 27 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.2532-449G>C		intron_variant	Intron 28 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.2895-449G>C		intron_variant	Intron 28 of 40	1	NM_001130823.3	ENSP00000352516.3

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

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.0800

Gnomad4 EAS exome AF: 0.414

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.0948

Gnomad4 NFE exome AF: 0.0498

Gnomad4 OTH exome AF: 0.0830

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

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.0644

Gnomad4 OTH AF: 0.128

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.38
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs10407514; hg19: chr19-10255112;