rs4804490

Variant names:

• chr19-10156335-C-A
• rs4804490
• NM_001130823.3:c.1399+56G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10156335-C-A
• chr19-10156335-C-G

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.1399+56G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0948 in 1,410,962 control chromosomes in the GnomAD database, including 10,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1498 hom., cov: 31)
  • Exomes 𝑓: 0.092 (8586 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198
• Publications: 14 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=-0.8).
• BP6: Variant 19-10156335-C-A is Benign according to our data. Variant chr19-10156335-C-A is described in ClinVar as Benign. ClinVar VariationId is 1251118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 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.1399+56G>T		intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.1351+56G>T		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.1351+56G>T		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.1399+56G>T		intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.1351+56G>T		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*1089+56G>T		intron	N/A	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17797 AN: 151786 Hom.: 1493 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0921 AC: 115908 AN: 1259060 Hom.: 8586 AF XY: 0.0949 AC XY: 60341 AN XY: 636082

African (AFR) AF: 0.144 AC: 4227 AN: 29322

American (AMR) AF: 0.231 AC: 10209 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2733 AN: 24560

East Asian (EAS) AF: 0.362 AC: 13814 AN: 38134

South Asian (SAS) AF: 0.197 AC: 16105 AN: 81698

European-Finnish (FIN) AF: 0.0850 AC: 4362 AN: 51310

Middle Eastern (MID) AF: 0.0854 AC: 455 AN: 5330

European-Non Finnish (NFE) AF: 0.0625 AC: 58228 AN: 931092

Other (OTH) AF: 0.108 AC: 5775 AN: 53462

GnomAD4 genome AF: 0.117 AC: 17843 AN: 151902 Hom.: 1498 Cov.: 31 AF XY: 0.123 AC XY: 9140 AN XY: 74248

African (AFR) AF: 0.143 AC: 5922 AN: 41410

American (AMR) AF: 0.192 AC: 2918 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3472

East Asian (EAS) AF: 0.398 AC: 2049 AN: 5154

South Asian (SAS) AF: 0.208 AC: 1000 AN: 4806

European-Finnish (FIN) AF: 0.0923 AC: 973 AN: 10544

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.0629 AC: 4275 AN: 67984

Other (OTH) AF: 0.111 AC: 234 AN: 2108

Alfa AF: 0.0426 Hom.: 46

Bravo AF: 0.127

Asia WGS AF: 0.264 AC: 917 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.2
DANN	Benign	0.53
PhyloP100		-0.20
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: rs4804490; hg19: chr19-10267011; COSMIC: COSV61579610; COSMIC: COSV61579610;