rs138453255

Positions:

chr9-128946225-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014908.4(DOLK):c.1079A>G(p.Tyr360Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000914 in 1,614,084 control chromosomes in the GnomAD database, including 7 homozygotes. 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 0.0011 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00089 ( 6 hom. )

Consequence

DOLK
NM_014908.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 5.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012760758).

BP6

Variant 9-128946225-T-C is Benign according to our data. Variant chr9-128946225-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}. Variant chr9-128946225-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00113 (172/152240) while in subpopulation AMR AF= 0.00353 (54/15286). AF 95% confidence interval is 0.00278. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOLK	NM_014908.4 linkuse as main transcript	c.1079A>G	p.Tyr360Cys	missense_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4 linkuse as main transcript	c.1079A>G	p.Tyr360Cys	missense_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00462

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00148

AC:

371

AN:

251306

Hom.:

AF XY:

0.00140

AC XY:

190

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.000892

AC:

1304

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

663

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00326

Gnomad4 ASJ exome

AF:

0.00635

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000939

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152240

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00462

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.00137

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00149

AC:

181

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DK1-congenital disorder of glycosylation

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	Variant summary: DOLK c.1079A>G (p.Tyr360Cys) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251306 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOLK causing DK1-Congenital Disorder Of Glycosylation phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1079A>G in individuals affected with DK1-Congenital Disorder Of Glycosylation and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four classified the variant as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2015	p.Tyr360Cys in exon 1 of DOLK: This variant is not expected to have clinical sig nificance because it has been identified in 0.38% (44/11578) of Latino chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs138453255). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	This variant is associated with the following publications: (PMID: 27212206, 25819062, 28820871) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DOLK: BP4 -

DOLK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.025

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.30

Sift

Uncertain

0.015

Sift4G

Uncertain

0.017

Polyphen

0.99

Vest4

0.59

MVP

0.75

MPC

1.1

ClinPred

0.12

GERP RS

5.2

Varity_R

0.35

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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