19-10154917-G-T

Variant names:

• chr19-10154917-G-T
• rs2228613
• NM_001130823.3:c.1632C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130823.3(DNMT1):​c.1632C>A​(p.Ile544Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 1,614,142 control chromosomes in the GnomAD database, including 6,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (462 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5797 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.17
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-10154917-G-T is Benign according to our data. Variant chr19-10154917-G-T is described in ClinVar as Benign. ClinVar VariationId is 137134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 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.1632C>A	p.Ile544Ile	synonymous	Exon 20 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.1584C>A	p.Ile528Ile	synonymous	Exon 19 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.1584C>A	p.Ile528Ile	synonymous	Exon 19 of 40	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.1632C>A	p.Ile544Ile	synonymous	Exon 20 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.1584C>A	p.Ile528Ile	synonymous	Exon 19 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*1322C>A		non_coding_transcript_exon	Exon 20 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.0682 AC: 10380 AN: 152150 Hom.: 462 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0464

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0708 AC: 17815 AN: 251480 AF XY: 0.0739

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.0964

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.0860 AC: 125773 AN: 1461874 Hom.: 5797 Cov.: 37 AF XY: 0.0860 AC XY: 62553 AN XY: 727240

African (AFR) AF: 0.0331 AC: 1109 AN: 33480

American (AMR) AF: 0.0339 AC: 1516 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1661 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0747 AC: 6443 AN: 86254

European-Finnish (FIN) AF: 0.0840 AC: 4487 AN: 53414

Middle Eastern (MID) AF: 0.0577 AC: 333 AN: 5768

European-Non Finnish (NFE) AF: 0.0950 AC: 105696 AN: 1112006

Other (OTH) AF: 0.0748 AC: 4519 AN: 60394

GnomAD4 genome AF: 0.0682 AC: 10384 AN: 152268 Hom.: 462 Cov.: 32 AF XY: 0.0678 AC XY: 5045 AN XY: 74444

African (AFR) AF: 0.0355 AC: 1474 AN: 41550

American (AMR) AF: 0.0463 AC: 708 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0686 AC: 331 AN: 4826

European-Finnish (FIN) AF: 0.0767 AC: 813 AN: 10600

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0974 AC: 6624 AN: 68030

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0820 Hom.: 388

Bravo AF: 0.0635

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0935

EpiControl AF: 0.0944

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs2228613; hg19: chr19-10265593; COSMIC: COSV61576246;