rs148646968

Positions:

chr9-128946431-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1

The NM_014908.4(DOLK):c.873C>T(p.Leu291Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,614,138 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).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

DOLK
NM_014908.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.598

Variant links:

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]

DOLK links:

ENSG00000251184 (HGNC:):

ENSG00000251184 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 9-128946431-G-A is Benign according to our data. Variant chr9-128946431-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464206.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

BP7

Synonymous conserved (PhyloP=0.598 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152286) while in subpopulation NFE AF= 0.000603 (41/68028). AF 95% confidence interval is 0.000457. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOLK	NM_014908.4 linkuse as main transcript	c.873C>T	p.Leu291Leu	synonymous_variant	1/1	ENST00000372586.4	NP_055723.1	Q9UPQ8A0A0S2Z597

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOLK	ENST00000372586.4 linkuse as main transcript	c.873C>T	p.Leu291Leu	synonymous_variant	1/1	6	NM_014908.4	ENSP00000361667.3		Q9UPQ8
ENSG00000251184	ENST00000482796.1 linkuse as main transcript	c.39-2758G>A		intron_variant		2		ENSP00000417556.2		H7C4K7

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00528

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000501

AC:

126

AN:

251316

Hom.:

AF XY:

0.000501

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00351

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000337

AC:

493

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000344

AC XY:

250

AN XY:

727226

show subpopulations

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:

0.00245

Gnomad4 NFE exome

AF:

0.000318

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152286

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00528

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000549

Hom.:

Bravo

AF:

0.000204

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DK1-congenital disorder of glycosylation

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 17, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 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

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.1

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over