rs142903301

Variant names:

• chr19-10139685-G-A
• rs142903301
• NM_001130823.3:c.3939C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10139685-G-A
• chr19-10139685-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.3939C>T​(p.Gly1313Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,040 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (11 hom., cov: 33)
  • Exomes 𝑓: 0.014 (158 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.833
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 19-10139685-G-A is Benign according to our data. Variant chr19-10139685-G-A is described in ClinVar as Benign. ClinVar VariationId is 257541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00941 (1434/152344) while in subpopulation NFE AF = 0.0163 (1111/68020). AF 95% confidence interval is 0.0155. There are 11 homozygotes in GnomAd4. There are 652 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1434 Unknown,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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.3939C>T	p.Gly1313Gly	synonymous	Exon 34 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.3891C>T	p.Gly1297Gly	synonymous	Exon 33 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.3891C>T	p.Gly1297Gly	synonymous	Exon 33 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.3939C>T	p.Gly1313Gly	synonymous	Exon 34 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.3891C>T	p.Gly1297Gly	synonymous	Exon 33 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*3629C>T		non_coding_transcript_exon	Exon 34 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1435 AN: 152226 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00912 AC: 2263 AN: 248052 AF XY: 0.00921

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00788

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.00828

GnomAD4 exome AF: 0.0136 AC: 19878 AN: 1460696 Hom.: 158 Cov.: 33 AF XY: 0.0133 AC XY: 9659 AN XY: 726650

African (AFR) AF: 0.00251 AC: 84 AN: 33466

American (AMR) AF: 0.00323 AC: 144 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26116

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86106

European-Finnish (FIN) AF: 0.00917 AC: 486 AN: 53010

Middle Eastern (MID) AF: 0.00127 AC: 7 AN: 5498

European-Non Finnish (NFE) AF: 0.0164 AC: 18206 AN: 1111856

Other (OTH) AF: 0.00995 AC: 600 AN: 60320

GnomAD4 genome AF: 0.00941 AC: 1434 AN: 152344 Hom.: 11 Cov.: 33 AF XY: 0.00875 AC XY: 652 AN XY: 74506

African (AFR) AF: 0.00315 AC: 131 AN: 41584

American (AMR) AF: 0.00562 AC: 86 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1111 AN: 68020

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.0130 Hom.: 8

Bravo AF: 0.00881

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 2

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

Other links and lift over

dbSNP: rs142903301; hg19: chr19-10250361;