rs200278288

Variant names:

• chr9-128946779-A-C
• rs200278288
• NM_014908.4:c.525T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_014908.4(DOLK):​c.525T>G​(p.Val175Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: DOLK NM_014908.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.698
• Publications: 0 publications found

Genes affected

DOLK (HGNC:23406): (dolichol kinase) The protein encoded by this gene catalyzes the CTP-mediated phosphorylation of dolichol, and is involved in the synthesis of Dol-P-Man, which is an essential glycosyl carrier lipid for C- and O-mannosylation, N- and O-linked glycosylation of proteins, and for the biosynthesis of glycosyl phosphatidylinositol anchors in endoplasmic reticulum. Mutations in this gene are associated with dolichol kinase deficiency.[provided by RefSeq, Apr 2010]

DOLK Gene-Disease associations (from GenCC):

• DK1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251184 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-128946779-A-C is Benign according to our data. Variant chr9-128946779-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 384847.
• BP7: Synonymous conserved (PhyloP=0.698 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000441 (67/152072) while in subpopulation NFE AF = 0.000691 (47/67972). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014908.4. 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
	DOLK	NM_014908.4	MANE Select	c.525T>G	p.Val175Val	synonymous	Exon 1 of 1	NP_055723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOLK	ENST00000372586.4	TSL:6 MANE Select	c.525T>G	p.Val175Val	synonymous	Exon 1 of 1	ENSP00000361667.3
	ENSG00000251184	ENST00000482796.1	TSL:2	c.39-2410A>C		intron	N/A	ENSP00000417556.2

Frequencies

GnomAD3 genomes AF: 0.000448 AC: 68 AN: 151954 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000478 AC: 120 AN: 251234 AF XY: 0.000552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 244 AN XY: 727200

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00244 AC: 130 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000281 AC: 313 AN: 1112010

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000441 AC: 67 AN: 152072 Hom.: 0 Cov.: 31 AF XY: 0.000444 AC XY: 33 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000580 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	DK1-congenital disorder of glycosylation (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Benign	0.74
PhyloP100		0.70
Mutation Taster		=99/1	polymorphism

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: rs200278288; hg19: chr9-131709058;