rs9305012

Positions:

• chr19-10150193-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001130823.3(DNMT1):​c.2266-225A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,176 control chromosomes in the GnomAD database, including 2,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2115 hom., cov: 32)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.426

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-10150193-T-C is Benign according to our data. Variant chr19-10150193-T-C is described in ClinVar as [Benign]. Clinvar id is 1276448.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.2266-225A>G		intron_variant		ENST00000359526.9
DNMT1	NM_001318730.2	c.2218-225A>G		intron_variant
DNMT1	NM_001318731.2	c.1903-225A>G		intron_variant
DNMT1	NM_001379.4	c.2218-225A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.2266-225A>G		intron_variant		1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21182 AN: 152058 Hom.: 2094 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.140 AC: 21261 AN: 152176 Hom.: 2115 Cov.: 32 AF XY: 0.147 AC XY: 10924 AN XY: 74376

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.0645

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0836 Hom.: 1602

Bravo AF: 0.147

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.48

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: rs9305012; hg19: chr19-10260869;