rs10423341

Variant names:

• chr19-10156590-C-A
• rs10423341
• NM_001130823.3:c.1281-81G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10156590-C-A
• chr19-10156590-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.1281-81G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 981,090 control chromosomes in the GnomAD database, including 9,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1890 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7343 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.651
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-10156590-C-A is Benign according to our data. Variant chr19-10156590-C-A is described in ClinVar as Benign. ClinVar VariationId is 1272273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1281-81G>T		intron_variant	Intron 17 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1233-81G>T		intron_variant	Intron 16 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.1233-81G>T		intron_variant	Intron 16 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.918-81G>T		intron_variant	Intron 17 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1281-81G>T		intron_variant	Intron 17 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19892 AN: 152016 Hom.: 1870 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.103 AC: 85478 AN: 828956 Hom.: 7343 AF XY: 0.106 AC XY: 46250 AN XY: 437384

African (AFR) AF: 0.193 AC: 4069 AN: 21116

American (AMR) AF: 0.233 AC: 9976 AN: 42778

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2383 AN: 21558

East Asian (EAS) AF: 0.360 AC: 12936 AN: 35898

South Asian (SAS) AF: 0.196 AC: 14339 AN: 73084

European-Finnish (FIN) AF: 0.0857 AC: 4348 AN: 50748

Middle Eastern (MID) AF: 0.0897 AC: 395 AN: 4406

European-Non Finnish (NFE) AF: 0.0604 AC: 32671 AN: 540534

Other (OTH) AF: 0.112 AC: 4361 AN: 38834

GnomAD4 genome AF: 0.131 AC: 19971 AN: 152134 Hom.: 1890 Cov.: 32 AF XY: 0.137 AC XY: 10160 AN XY: 74368

African (AFR) AF: 0.191 AC: 7917 AN: 41468

American (AMR) AF: 0.197 AC: 3003 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2059 AN: 5184

South Asian (SAS) AF: 0.209 AC: 1005 AN: 4820

European-Finnish (FIN) AF: 0.0925 AC: 980 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0629 AC: 4281 AN: 68014

Other (OTH) AF: 0.120 AC: 252 AN: 2108

Alfa AF: 0.0884 Hom.: 115

Bravo AF: 0.142

Asia WGS AF: 0.273 AC: 948 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.95
CADD	Benign	0.23
DANN	Benign	0.66
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10423341; hg19: chr19-10267266; COSMIC: COSV61584710; COSMIC: COSV61584710;