rs17485436

Positions:

chr9-128946633-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_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. 12/21 in silico tools predict 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:2B:3

Conservation

PhyloP100: 5.86

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 links:

ENSG00000251184 (HGNC:):

ENSG00000251184 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 227336.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOLK	NM_014908.4 linkuse as main transcript	c.671A>T	p.Asp224Val	missense_variant	1/1	ENST00000372586.4	NP_055723.1	Q9UPQ8A0A0S2Z597

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOLK	ENST00000372586.4 linkuse as main transcript	c.671A>T	p.Asp224Val	missense_variant	1/1	6	NM_014908.4	ENSP00000361667.3		Q9UPQ8
ENSG00000251184	ENST00000482796.1 linkuse as main transcript	c.39-2556T>A		intron_variant		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

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251478

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135914

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 SAS 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

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000684

AC:

104

AN:

152132

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2016	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2024	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2023

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. -

DK1-congenital disorder of glycosylation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2020

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over