rs139787271

chr9-128946604-T-Cchr9-128946604-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014908.4(DOLK):c.700A>G(p.Met234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M234I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: DOLK NM_014908.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.62

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010249466).
• BP6: Variant 9-128946604-T-C is Benign according to our data. Variant chr9-128946604-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95647.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (155/151996) while in subpopulation NFE AF= 0.00175 (119/67946). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOLK	NM_014908.4	c.700A>G	p.Met234Val	missense_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4	c.700A>G	p.Met234Val	missense_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00120 AC: 303 AN: 251482 Hom.: 3 AF XY: 0.00123 AC XY: 167 AN XY: 135912

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00165 AC: 2415 AN: 1461894 Hom.: 6 Cov.: 31 AF XY: 0.00163 AC XY: 1189 AN XY: 727248

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00102 AC: 155 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.000956 AC XY: 71 AN XY: 74292

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00208

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.000854

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

DK1-congenital disorder of glycosylation Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	This variant is associated with the following publications: (PMID: 23757202, 23806237) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2012	- -

DOLK-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2022

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

Nov 21, 2023

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	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	14
Dann	Benign	0.80
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.14
Sift	Benign	0.78	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.068
MVP		0.61
MPC		0.37
ClinPred		0.014	T
GERP RS		2.6
Varity_R		0.028
gMVP		0.34

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: rs139787271; hg19: chr9-131708883;