rs2241531

Variant names:

• chr19-10160358-C-G
• rs2241531
• NM_001130823.3:c.1043+26G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10160358-C-G
• chr19-10160358-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.1043+26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,140 control chromosomes in the GnomAD database, including 13,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2143 hom., cov: 33)
  • Exomes 𝑓: 0.096 (11196 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.602
• Publications: 23 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=-0.93).
• BP6: Variant 19-10160358-C-G is Benign according to our data. Variant chr19-10160358-C-G is described in ClinVar as Benign. ClinVar VariationId is 1246124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1043+26G>C		intron_variant	Intron 14 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.995+26G>C		intron_variant	Intron 13 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.995+26G>C		intron_variant	Intron 13 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.680+26G>C		intron_variant	Intron 14 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1043+26G>C		intron_variant	Intron 14 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21256 AN: 152076 Hom.: 2122 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0644

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.153 AC: 38540 AN: 251248 AF XY: 0.149

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0624

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.0960 AC: 140223 AN: 1460946 Hom.: 11196 Cov.: 32 AF XY: 0.0984 AC XY: 71550 AN XY: 726790

African (AFR) AF: 0.205 AC: 6874 AN: 33456

American (AMR) AF: 0.235 AC: 10505 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2922 AN: 26128

East Asian (EAS) AF: 0.413 AC: 16383 AN: 39666

South Asian (SAS) AF: 0.206 AC: 17781 AN: 86188

European-Finnish (FIN) AF: 0.130 AC: 6908 AN: 53322

Middle Eastern (MID) AF: 0.0929 AC: 536 AN: 5768

European-Non Finnish (NFE) AF: 0.0638 AC: 70959 AN: 1111362

Other (OTH) AF: 0.122 AC: 7355 AN: 60350

GnomAD4 genome AF: 0.140 AC: 21335 AN: 152194 Hom.: 2143 Cov.: 33 AF XY: 0.148 AC XY: 10984 AN XY: 74414

African (AFR) AF: 0.200 AC: 8315 AN: 41510

American (AMR) AF: 0.201 AC: 3071 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2289 AN: 5174

South Asian (SAS) AF: 0.216 AC: 1043 AN: 4830

European-Finnish (FIN) AF: 0.140 AC: 1487 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0645 AC: 4384 AN: 68018

Other (OTH) AF: 0.129 AC: 272 AN: 2110

Alfa AF: 0.0577 Hom.: 88

Bravo AF: 0.148

Asia WGS AF: 0.323 AC: 1124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		-0.60
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: rs2241531; hg19: chr19-10271034; COSMIC: COSV61576782; COSMIC: COSV61576782;