rs9305012

Variant names:

• chr19-10150193-T-C
• rs9305012
• NM_001130823.3:c.2266-225A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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 -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 VariationId 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 rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.2266-225A>G		intron_variant	Intron 24 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.2218-225A>G		intron_variant	Intron 23 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.2218-225A>G		intron_variant	Intron 23 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.1903-225A>G		intron_variant	Intron 24 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.2266-225A>G		intron_variant	Intron 24 of 40	1	NM_001130823.3	ENSP00000352516.3

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

African (AFR) AF: 0.200 AC: 8313 AN: 41536

American (AMR) AF: 0.201 AC: 3064 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3464

East Asian (EAS) AF: 0.431 AC: 2229 AN: 5166

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4824

European-Finnish (FIN) AF: 0.140 AC: 1484 AN: 10592

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0645 AC: 4390 AN: 68010

Other (OTH) AF: 0.127 AC: 267 AN: 2110

Alfa AF: 0.0923 Hom.: 2917

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

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.48
PhyloP100		-0.43
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: rs9305012; hg19: chr19-10260869;