rs17485436

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_014908.4(DOLK):c.671A>T(p.Asp224Val) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,614,026 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 0.00068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

DOLK
NM_014908.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 5.86

Publications

2 publications found

Variant links:

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

DOLK links:

ENSG00000251184 (HGNC:):

ENSG00000251184 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030765384).

BP6

Variant 9-128946633-T-A is Benign according to our data. Variant chr9-128946633-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227336.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000684 (104/152132) while in subpopulation AFR AF = 0.00243 (101/41502). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOLK	NM_014908.4 link	c.671A>T	p.Asp224Val	missense_variant	Exon 1 of 1	ENST00000372586.4	NP_055723.1	Q9UPQ8A0A0S2Z597

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOLK	ENST00000372586.4 link	c.671A>T	p.Asp224Val	missense_variant	Exon 1 of 1	6	NM_014908.4	ENSP00000361667.3		Q9UPQ8
ENSG00000251184	ENST00000482796.1 link	c.39-2556T>A		intron_variant	Intron 1 of 4	2		ENSP00000417556.2		H7C4K7

Frequencies

GnomAD3 genomes

AF:

0.000684

AC:

104

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000215

AC:

AN:

251478

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000684

AC:

104

AN:

152132

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41502

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000657

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Feb 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp224Val in exon 1 of DOLK: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (32/10394) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs17485436). -

DK1-congenital disorder of glycosylation

Uncertain:1Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DOLK c.671A>T; p.Asp224Val variant (rs17485436), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 227336). This variant is observed in the African population with an allele frequency of 0.3% (73/24946 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.51). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Cardiovascular phenotype

Uncertain:1

May 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D224V variant (also known as c.671A>T), located in coding exon 1 of the DOLK gene, results from an A to T substitution at nucleotide position 671. The aspartic acid at codon 224 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Oct 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported as a likely benign variant in ClinVar but additional evidence is not available (SCV000270160.2, SCV000761345.1; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

0.095

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.031

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.9

PhyloP100

5.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.51

Sift

Benign

0.16

Sift4G

Uncertain

0.012

Polyphen

0.26

Vest4

0.68

MVP

0.85

MPC

0.64

ClinPred

0.045

GERP RS

5.3

Varity_R

0.24

gMVP

0.55

Mutation Taster

=53/47

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over