rs145310298

Positions:

• chr9-128946673-G-A

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.631C>T​(p.Arg211Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,128 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts 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. R211H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (17 hom.)
• Consequence: DOLK NM_014908.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 3.35

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=0.015254825).
• BP6: Variant 9-128946673-G-A is Benign according to our data. Variant chr9-128946673-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95646.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00233 (354/152238) while in subpopulation AMR AF= 0.0036 (55/15276). AF 95% confidence interval is 0.00315. There are 2 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOLK	NM_014908.4	c.631C>T	p.Arg211Cys	missense_variant	1/1	ENST00000372586.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOLK	ENST00000372586.4	c.631C>T	p.Arg211Cys	missense_variant	1/1		NM_014908.4	P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152120 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00189 AC: 476 AN: 251394 Hom.: 1 AF XY: 0.00199 AC XY: 271 AN XY: 135870

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00342 AC: 5003 AN: 1461890 Hom.: 17 Cov.: 31 AF XY: 0.00332 AC XY: 2417 AN XY: 727246

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00409

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00233 AC: 354 AN: 152238 Hom.: 2 Cov.: 31 AF XY: 0.00195 AC XY: 145 AN XY: 74436

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00292 Hom.: 0

Bravo AF: 0.00226

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	This variant is associated with the following publications: (PMID: 23757202) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	DOLK: BS2 -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	Variant summary: DOLK c.631C>T (p.Arg211Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251394 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.69 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOLK causing DK1-Congenital Disorder Of Glycosylation (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.631C>T in individuals affected with DK1-Congenital Disorder Of Glycosylation and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; five submitters classified the variant as likely benign and one classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2015	p.Arg211Cys in exon 1 of DOLK: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (162/66700) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145310298). Additionally, arginine (Arg) at position 211 is not conserve d in mammals or evolutionarily distant species, and 2 mammals (cape elephant shr ew and aardvark) carry a cysteine (Cys) despite high nearby amino acid conservat ion. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 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	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.49	N
REVEL	Uncertain	0.59
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.59	P
Vest4		0.24
MVP		0.85
MPC		0.51
ClinPred		0.014	T
GERP RS		4.4
Varity_R		0.067
gMVP		0.60

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: rs145310298; hg19: chr9-131708952; COSMIC: COSV58281258; COSMIC: COSV58281258;