rs145292760

chr9-128945823-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_014908.4(DOLK):c.1481A>G(p.Asp494Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D494D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: DOLK NM_014908.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 8.01

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03287089).
• BP6: Variant 9-128945823-T-C is Benign according to our data. Variant chr9-128945823-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000388 (59/152156) while in subpopulation NFE AF= 0.000147 (10/68028). AF 95% confidence interval is 0.0000791. There are 1 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOLK	NM_014908.4	c.1481A>G	p.Asp494Gly	missense_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4	c.1481A>G	p.Asp494Gly	missense_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152156 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000521 AC: 131 AN: 251476 Hom.: 0 AF XY: 0.000500 AC XY: 68 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.000260 AC XY: 189 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152156 Hom.: 1 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DK1-congenital disorder of glycosylation Uncertain:1 Benign: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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: DOLK c.1481A>G (p.Asp494Gly) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 152156 control chromosomes, predominantly at a frequency of 0.013 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 12 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 a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1481A>G has been reported in the literature in one individual affected with DK1-Congenital Disorder Of Glycosylation (Jones_2013). The report does not provide unequivocal conclusions about association of the variant with DK1-Congenital Disorder Of Glycosylation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23806237). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2018	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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.033	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.53
Sift	Benign	0.50	T
Sift4G	Benign	0.19	T
Polyphen		0.20	B
Vest4		0.94
MVP		0.80
MPC		1.3
ClinPred		0.081	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.84

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: rs145292760; hg19: chr9-131708102;