rs148171062

Positions:

• chr9-128947118-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014908.4(DOLK):​c.186G>A​(p.Arg62=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,614,016 control chromosomes in the GnomAD database, including 19 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 0.0027 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (16 hom.)
• Consequence: DOLK NM_014908.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.0120

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-128947118-C-T is Benign according to our data. Variant chr9-128947118-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95644.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}. Variant chr9-128947118-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00272 (414/152272) while in subpopulation NFE AF= 0.00266 (181/68022). AF 95% confidence interval is 0.00234. There are 3 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOLK	NM_014908.4	c.186G>A	p.Arg62=	synonymous_variant	1/1	ENST00000372586.4	NP_055723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOLK	ENST00000372586.4	c.186G>A	p.Arg62=	synonymous_variant	1/1		NM_014908.4	ENSP00000361667	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152154 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00333 AC: 836 AN: 251194 Hom.: 7 AF XY: 0.00333 AC XY: 452 AN XY: 135798

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00281 AC: 4105 AN: 1461744 Hom.: 16 Cov.: 31 AF XY: 0.00268 AC XY: 1946 AN XY: 727180

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152272 Hom.: 3 Cov.: 31 AF XY: 0.00352 AC XY: 262 AN XY: 74444

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DK1-congenital disorder of glycosylation Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 22, 2015	p.Arg62Arg in exon 1 of DOLK: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.4% (279/66586) of European chromosomes, including 1 homozygote by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148171062). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DOLK: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

DOLK-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

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

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

This alteration is classified as 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
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.94

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

Other links and lift over

dbSNP: rs148171062; hg19: chr9-131709397;