10-26697805-T-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.94T>A(p.Leu32Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L32V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00300

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=0.19783178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDSS1	NM_014317.5	c.94T>A	p.Leu32Met	missense_variant	1/12	ENST00000376215.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDSS1	ENST00000376215.10	c.94T>A	p.Leu32Met	missense_variant	1/12	1	NM_014317.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deafness-encephaloneuropathy-obesity-valvulopathy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	5.7
Dann	Benign	0.73
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.18	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.19
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.33	B
Vest4		0.16
MutPred		0.16		Gain of MoRF binding (P = 0.1075);
MVP		0.76
MPC		0.46
ClinPred		0.21	T
GERP RS		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.083
gMVP		0.19

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: rs1834912984; hg19: chr10-26986734;