NM_014317.5:c.74C>T

Variant names:

• chr10-26697785-C-T
• rs863224160
• NM_014317.5:c.74C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014317.5(PDSS1):​c.74C>T​(p.Ser25Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000535 in 1,307,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.471
• Publications: 1 publications found

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]

PDSS1 Gene-Disease associations (from GenCC):

• deafness-encephaloneuropathy-obesity-valvulopathy syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000279212 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15941522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014317.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS1	NM_014317.5	MANE Select	c.74C>T	p.Ser25Phe	missense	Exon 1 of 12	NP_055132.2	Q5T2R2-1
	PDSS1	NM_001321978.2		c.74C>T	p.Ser25Phe	missense	Exon 1 of 10	NP_001308907.1	Q5T2R2-2
	PDSS1	NM_001321979.2		c.-520C>T		5_prime_UTR	Exon 1 of 12	NP_001308908.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS1	ENST00000376215.10	TSL:1 MANE Select	c.74C>T	p.Ser25Phe	missense	Exon 1 of 12	ENSP00000365388.5	Q5T2R2-1
	PDSS1	ENST00000917009.1		c.74C>T	p.Ser25Phe	missense	Exon 1 of 11	ENSP00000587068.1
	PDSS1	ENST00000869579.1		c.74C>T	p.Ser25Phe	missense	Exon 1 of 10	ENSP00000539638.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151948 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000519 AC: 6 AN: 1155616 Hom.: 0 Cov.: 30 AF XY: 0.00000537 AC XY: 3 AN XY: 558686

African (AFR) AF: 0.00 AC: 0 AN: 23574

American (AMR) AF: 0.00 AC: 0 AN: 11548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16218

East Asian (EAS) AF: 0.0000377 AC: 1 AN: 26540

South Asian (SAS) AF: 0.0000771 AC: 3 AN: 38910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3206

European-Non Finnish (NFE) AF: 0.00000207 AC: 2 AN: 963998

Other (OTH) AF: 0.00 AC: 0 AN: 46710

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74206

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.9
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.47
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.19		Loss of phosphorylation at S25 (P = 0.0036)
MVP		0.39
MPC		0.53
ClinPred		0.15	T
GERP RS		-1.9
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.25
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs863224160; hg19: chr10-26986714;