rs74505694

Variant names:

• chr19-10149661-G-A
• rs74505694
• NM_001130823.3:c.2382-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.2382-4C>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 0.00405 in 1,613,518 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (113 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005348
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0740
• Publications: 2 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=-0.77).
• BP6: Variant 19-10149661-G-A is Benign according to our data. Variant chr19-10149661-G-A is described in ClinVar as Benign. ClinVar VariationId is 327902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00579 (882/152304) while in subpopulation EAS AF = 0.0334 (173/5174). AF 95% confidence interval is 0.0294. There are 18 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 882 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.2382-4C>T		splice_region intron	N/A	NP_001124295.1
	DNMT1	NM_001318730.2		c.2334-4C>T		splice_region intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.2334-4C>T		splice_region intron	N/A	NP_001370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.2382-4C>T		splice_region intron	N/A	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.2334-4C>T		splice_region intron	N/A	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.*2072-4C>T		splice_region intron	N/A	ENSP00000466657.1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152186 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0334

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00872 AC: 2186 AN: 250756 AF XY: 0.00855

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00387 AC: 5651 AN: 1461214 Hom.: 113 Cov.: 32 AF XY: 0.00392 AC XY: 2853 AN XY: 726896

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0354 AC: 1404 AN: 39700

South Asian (SAS) AF: 0.00855 AC: 737 AN: 86238

European-Finnish (FIN) AF: 0.0441 AC: 2349 AN: 53250

Middle Eastern (MID) AF: 0.000935 AC: 5 AN: 5346

European-Non Finnish (NFE) AF: 0.000603 AC: 671 AN: 1112008

Other (OTH) AF: 0.00756 AC: 456 AN: 60340

GnomAD4 genome AF: 0.00579 AC: 882 AN: 152304 Hom.: 18 Cov.: 32 AF XY: 0.00786 AC XY: 585 AN XY: 74474

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.00307 AC: 47 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5174

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4822

European-Finnish (FIN) AF: 0.0473 AC: 502 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68040

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00193

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)
-	-	2	not specified (2)
-	-	1	DNMT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		-0.074
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.014
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: rs74505694; hg19: chr19-10260337;