rs117294281

Variant names:

• chr19-10166590-G-A
• rs117294281
• NM_001130823.3:c.891+8C>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.891+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,950 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (59 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009541
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.854
• Publications: 4 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=-0.82).
• BP6: Variant 19-10166590-G-A is Benign according to our data. Variant chr19-10166590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0608 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.891+8C>T		splice_region intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.843+8C>T		splice_region intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.843+8C>T		splice_region 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.891+8C>T		splice_region intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.843+8C>T		splice_region intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.69+8C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00487 AC: 1224 AN: 251472 AF XY: 0.00520

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00511

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00431 AC: 6295 AN: 1461702 Hom.: 59 Cov.: 32 AF XY: 0.00451 AC XY: 3281 AN XY: 727158

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00389 AC: 174 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 592 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00653 AC: 563 AN: 86256

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53400

Middle Eastern (MID) AF: 0.0663 AC: 382 AN: 5762

European-Non Finnish (NFE) AF: 0.00371 AC: 4123 AN: 1111898

Other (OTH) AF: 0.00613 AC: 370 AN: 60366

GnomAD4 genome AF: 0.00315 AC: 479 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74434

African (AFR) AF: 0.000529 AC: 22 AN: 41558

American (AMR) AF: 0.00301 AC: 46 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68010

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00578 Hom.: 2

Bravo AF: 0.00316

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00646

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)
-	-	1	DNMT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.40
PhyloP100		0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000095
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117294281; hg19: chr19-10277266;