rs531969689

chr9-128947302-A-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 6P and 16B. PVS1_Strong PS1_Moderate BP6_Very_Strong BS1 BS2

The NM_014908.4(DOLK):c.1_2insA(p.Met1?) variant causes a frameshift, start lost, start retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 1,612,158 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (45 hom.)
• Consequence: DOLK NM_014908.4 frameshift, start_lost, start_retained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.62

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 -10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_014908.4 (DOLK) was described as [Likely_pathogenic] in ClinVar as 100664
• BP6: Variant 9-128947302-A-AT is Benign according to our data. Variant chr9-128947302-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 167006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00547 (833/152158) while in subpopulation NFE AF= 0.00916 (623/67978). AF 95% confidence interval is 0.00857. There are 2 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOLK	NM_014908.4	c.1_2insA	p.Met1?	frameshift_variant, start_lost, start_retained_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4	c.1_2insA	p.Met1?	frameshift_variant, start_lost, start_retained_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 833 AN: 152040 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00916

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00653 AC: 1614 AN: 247242 Hom.: 10 AF XY: 0.00630 AC XY: 849 AN XY: 134840

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00802

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00777

GnomAD4 exome AF: 0.00741 AC: 10819 AN: 1460000 Hom.: 45 Cov.: 31 AF XY: 0.00732 AC XY: 5319 AN XY: 726242

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00832

Gnomad4 NFE exome AF: 0.00879

Gnomad4 OTH exome AF: 0.00562

GnomAD4 genome AF: 0.00547 AC: 833 AN: 152158 Hom.: 2 Cov.: 31 AF XY: 0.00546 AC XY: 406 AN XY: 74408

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00886

Gnomad4 NFE AF: 0.00916

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00705 Hom.: 1

Bravo AF: 0.00467

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: The DOLK c.1dupA variant allele was found at a frequency of 0.0065 in 247242 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOLK causing Cardiomyopathy phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1dupA in individuals affected with Cardiomyopathy 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. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2015	c.1_2insA in exon 1 of DOLK: This variant is not expected to have clinical signi ficance because it does not alter the start codon and has been identified in 1.3 % (823/63350) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs531969689). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DOLK: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 30, 2016	- -

DK1-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2018

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

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: rs531969689; hg19: chr9-131709581;