rs147630977

Positions:

• chr9-128945854-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014908.4(DOLK):​c.1450A>G​(p.Ile484Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,614,226 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00096 (16 hom.)
• Consequence: DOLK NM_014908.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.84

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008740902).
• BP6: Variant 9-128945854-T-C is Benign according to our data. Variant chr9-128945854-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 226616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000755 (115/152334) while in subpopulation SAS AF= 0.0104 (50/4830). AF 95% confidence interval is 0.00807. There are 3 homozygotes in gnomad4. There are 67 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	UniProt
DOLK	NM_014908.4	c.1450A>G	p.Ile484Val	missense_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4	c.1450A>G	p.Ile484Val	missense_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152216 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00168 AC: 422 AN: 251468 Hom.: 10 AF XY: 0.00216 AC XY: 293 AN XY: 135922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000963 AC: 1408 AN: 1461892 Hom.: 16 Cov.: 31 AF XY: 0.00123 AC XY: 894 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00910

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152334 Hom.: 3 Cov.: 31 AF XY: 0.000899 AC XY: 67 AN XY: 74492

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000727 Hom.: 2

Bravo AF: 0.000487

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2015	p.Ile484Val in exon 1 of DOLK: This variant is not expected to have clinical sig nificance it has been identified in 1.1% (183/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs147630977). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2023	Variant summary: DOLK c.1450A>G (p.Ile484Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251468 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8.94 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 South Asian origin. c.1450A>G has been reported in the literature in an individual affected with L Carnitine deficiency, speaking delay, elevated pyruvic acid and ethylmalonic acid without strong evidence of causality (Jalkh_2019). This 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 has been ascertained in the context of this evaluation (PMID: 30665423). 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 likely benign. -

DK1-congenital disorder of glycosylation Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

DOLK: BS1, BS2 -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 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	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.057
Sift	Benign	0.16	T
Sift4G	Benign	0.24	T
Polyphen		0.017	B
Vest4		0.19
MVP		0.63
MPC		0.31
ClinPred		0.0092	T
GERP RS		3.1
Varity_R		0.045
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs147630977; hg19: chr9-131708133;