rs2114724

Variant names:

• chr19-10154572-T-C
• rs2114724
• NM_001130823.3:c.1832+14A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10154572-T-C
• chr19-10154572-T-A

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.1832+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,734 control chromosomes in the GnomAD database, including 206,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19882 hom., cov: 31)
  • Exomes 𝑓: 0.50 (186652 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.19
• Publications: 43 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10154572-T-C is Benign according to our data. Variant chr19-10154572-T-C is described in ClinVar as Benign. ClinVar VariationId is 257538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.1832+14A>G		intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.1784+14A>G		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.1784+14A>G		intron	N/A	NP_001370.1	P26358-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.1832+14A>G		intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.1784+14A>G		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*1522+14A>G		intron	N/A	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77170 AN: 151830 Hom.: 19850 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.484

GnomAD2 exomes AF: 0.518 AC: 129746 AN: 250402 AF XY: 0.517

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.512

GnomAD4 exome AF: 0.504 AC: 736772 AN: 1461786 Hom.: 186652 Cov.: 73 AF XY: 0.505 AC XY: 367328 AN XY: 727192

African (AFR) AF: 0.503 AC: 16839 AN: 33480

American (AMR) AF: 0.482 AC: 21576 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 14422 AN: 26136

East Asian (EAS) AF: 0.626 AC: 24836 AN: 39700

South Asian (SAS) AF: 0.537 AC: 46352 AN: 86258

European-Finnish (FIN) AF: 0.524 AC: 27941 AN: 53342

Middle Eastern (MID) AF: 0.562 AC: 3244 AN: 5768

European-Non Finnish (NFE) AF: 0.495 AC: 550649 AN: 1111984

Other (OTH) AF: 0.512 AC: 30913 AN: 60396

GnomAD4 genome AF: 0.508 AC: 77265 AN: 151948 Hom.: 19882 Cov.: 31 AF XY: 0.510 AC XY: 37890 AN XY: 74240

African (AFR) AF: 0.502 AC: 20795 AN: 41428

American (AMR) AF: 0.492 AC: 7499 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1915 AN: 3468

East Asian (EAS) AF: 0.676 AC: 3487 AN: 5160

South Asian (SAS) AF: 0.547 AC: 2636 AN: 4818

European-Finnish (FIN) AF: 0.516 AC: 5453 AN: 10564

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33780 AN: 67954

Other (OTH) AF: 0.489 AC: 1033 AN: 2114

Alfa AF: 0.502 Hom.: 3641

Bravo AF: 0.503

Asia WGS AF: 0.604 AC: 2098 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary sensory neuropathy-deafness-dementia syndrome (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant cerebellar ataxia, deafness and narcolepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.010
DANN	Benign	0.35
PhyloP100		-2.2
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: rs2114724; hg19: chr19-10265248; COSMIC: COSV61580166; COSMIC: COSV61580166;