10-26697781-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014317.5(PDSS1):c.70G>C(p.Gly24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,300,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.211

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2707129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDSS1	NM_014317.5	c.70G>C	p.Gly24Arg	missense_variant	1/12	ENST00000376215.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDSS1	ENST00000376215.10	c.70G>C	p.Gly24Arg	missense_variant	1/12	1	NM_014317.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151956 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 81 AN: 1148652 Hom.: 0 Cov.: 30 AF XY: 0.0000739 AC XY: 41 AN XY: 554618

Gnomad4 AFR exome AF: 0.0000428

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: 0.0000812

Gnomad4 OTH exome AF: 0.0000431

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152064 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.70G>C (p.G24R) alteration is located in exon 1 (coding exon 1) of the PDSS1 gene. This alteration results from a G to C substitution at nucleotide position 70, causing the glycine (G) at amino acid position 24 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 24 of the PDSS1 protein (p.Gly24Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDSS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1364494). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Deafness-encephaloneuropathy-obesity-valvulopathy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.20
Sift	Benign	0.040	D
Sift4G	Benign	0.38	T
Polyphen		0.66	P
Vest4		0.20
MutPred		0.24		Gain of methylation at G24 (P = 0.0106);
MVP		0.76
MPC		0.60
ClinPred		0.56	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.061
gMVP		0.23

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: rs1002908038; hg19: chr10-26986710;