10-26697800-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014317.5(PDSS1):c.89G>T(p.Gly30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,344,526 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (138 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (105 hom.)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.612

Genes affected

PDSS1 (HGNC:17759): (decaprenyl diphosphate synthase subunit 1) The protein encoded by this gene is an enzyme that elongates the prenyl side-chain of coenzyme Q, or ubiquinone, one of the key elements in the respiratory chain. The gene product catalyzes the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. The protein may be peripherally associated with the inner mitochondrial membrane, though no transit peptide has been definitively identified to date. Defects in this gene are a cause of coenzyme Q10 deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016926825).
• BP6: Variant 10-26697800-G-T is Benign according to our data. Variant chr10-26697800-G-T is described in ClinVar as [Benign]. Clinvar id is 138687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26697800-G-T is described in Lovd as [Likely_benign]. Variant chr10-26697800-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDSS1	NM_014317.5	c.89G>T	p.Gly30Val	missense_variant	1/12	ENST00000376215.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDSS1	ENST00000376215.10	c.89G>T	p.Gly30Val	missense_variant	1/12	1	NM_014317.5	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3387 AN: 151954 Hom.: 137 Cov.: 33

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00715

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00243 AC: 105 AN: 43154 Hom.: 5 AF XY: 0.00216 AC XY: 54 AN XY: 24944

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00227 AC: 2707 AN: 1192464 Hom.: 105 Cov.: 30 AF XY: 0.00207 AC XY: 1200 AN XY: 579458

Gnomad4 AFR exome AF: 0.0851

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00242

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.00548

GnomAD4 genome AF: 0.0223 AC: 3390 AN: 152062 Hom.: 138 Cov.: 33 AF XY: 0.0214 AC XY: 1591 AN XY: 74346

Gnomad4 AFR AF: 0.0779

Gnomad4 AMR AF: 0.00714

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00996

Alfa AF: 0.00335 Hom.: 2

Bravo AF: 0.0259

ExAC AF: 0.00138 AC: 22

Asia WGS AF: 0.00347 AC: 12 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Deafness-encephaloneuropathy-obesity-valvulopathy syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 26, 2016	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2013

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.45	B
Vest4		0.34
MVP		0.83
MPC		1.5
ClinPred		0.032	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.32

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: rs17855857; hg19: chr10-26986729;