rs16999358

Variant names:

• chr19-10162679-G-A
• rs16999358
• NM_001130823.3:c.996C>T

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.996C>T​(p.Asp332Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,611,458 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (78 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.194
• Publications: 7 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=-0.63).
• BP6: Variant 19-10162679-G-A is Benign according to our data. Variant chr19-10162679-G-A is described in ClinVar as Benign. ClinVar VariationId is 327917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0578 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.996C>T	p.Asp332Asp	synonymous	Exon 13 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.948C>T	p.Asp316Asp	synonymous	Exon 12 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.948C>T	p.Asp316Asp	synonymous	Exon 12 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.996C>T	p.Asp332Asp	synonymous	Exon 13 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.948C>T	p.Asp316Asp	synonymous	Exon 12 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.174C>T		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 416 AN: 150566 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000501

Gnomad OTH AF: 0.00339

GnomAD2 exomes AF: 0.00625 AC: 1570 AN: 251268 AF XY: 0.00583

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.0691

Gnomad FIN exome AF: 0.00636

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00236 AC: 3454 AN: 1460820 Hom.: 78 Cov.: 34 AF XY: 0.00238 AC XY: 1729 AN XY: 726762

African (AFR) AF: 0.000179 AC: 6 AN: 33464

American (AMR) AF: 0.000112 AC: 5 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 156 AN: 26120

East Asian (EAS) AF: 0.0598 AC: 2371 AN: 39670

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86250

European-Finnish (FIN) AF: 0.00674 AC: 358 AN: 53154

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111364

Other (OTH) AF: 0.00378 AC: 228 AN: 60342

GnomAD4 genome AF: 0.00275 AC: 415 AN: 150638 Hom.: 9 Cov.: 31 AF XY: 0.00343 AC XY: 252 AN XY: 73436

African (AFR) AF: 0.0000487 AC: 2 AN: 41076

American (AMR) AF: 0.000529 AC: 8 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.0548 AC: 282 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00631 AC: 63 AN: 9988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000501 AC: 34 AN: 67808

Other (OTH) AF: 0.00336 AC: 7 AN: 2082

Alfa AF: 0.00127 Hom.: 2

Bravo AF: 0.00346

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.2
DANN	Benign	0.49
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
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: rs16999358; hg19: chr19-10273355;