rs387907030

Positions:

• chr9-128946082-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014908.4(DOLK):​c.1222C>G​(p.His408Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DOLK NM_014908.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.91

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]

ENSG00000251184 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 9-128946082-G-C is Pathogenic according to our data. Variant chr9-128946082-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30850.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOLK	NM_014908.4	c.1222C>G	p.His408Asp	missense_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.1222C>G	p.His408Asp	missense_variant	1/1	6	NM_014908.4	ENSP00000361667.3
ENSG00000251184	ENST00000482796.1	c.39-3107G>C		intron_variant		2		ENSP00000417556.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

DK1-congenital disorder of glycosylation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 19, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.84
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.66		Loss of helix (P = 0.1706);
MVP		0.88
MPC		1.4
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.63
gMVP		0.95

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

Other links and lift over

dbSNP: rs387907030; hg19: chr9-131708361;