10-26697767-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014317.5(PDSS1):c.56G>A(p.Arg19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000614 in 1,139,422 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000061 (1 hom.)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.965

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17230782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDSS1	NM_014317.5	c.56G>A	p.Arg19Gln	missense_variant	1/12	ENST00000376215.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDSS1	ENST00000376215.10	c.56G>A	p.Arg19Gln	missense_variant	1/12	1	NM_014317.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000211 AC: 1 AN: 4734 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000614 AC: 7 AN: 1139422 Hom.: 1 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 549402

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: 0.00

Gnomad4 NFE exome AF: 0.00000731

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.56G>A (p.R19Q) alteration is located in exon 1 (coding exon 1) of the PDSS1 gene. This alteration results from a G to A substitution at nucleotide position 56, causing the arginine (R) at amino acid position 19 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.097
Sift	Benign	0.36	T
Sift4G	Benign	0.21	T
Polyphen		0.0060	B
Vest4		0.24
MutPred		0.16		Loss of methylation at R19 (P = 0.0159);
MVP		0.70
MPC		0.55
ClinPred		0.081	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.032
gMVP		0.31

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: rs1482484479; hg19: chr10-26986696;