10-26697730-C-T

Variant names:

• chr10-26697730-C-T
• rs1227021452
• NM_014317.5:c.19C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014317.5(PDSS1):​c.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,143,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28750804).

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.19C>T	p.Arg7Trp	missense	Exon 1 of 12	NP_055132.2	Q5T2R2-1
	PDSS1	NM_001321978.2		c.19C>T	p.Arg7Trp	missense	Exon 1 of 10	NP_001308907.1	Q5T2R2-2
	PDSS1	NM_001321979.2		c.-575C>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.19C>T	p.Arg7Trp	missense	Exon 1 of 12	ENSP00000365388.5	Q5T2R2-1
	PDSS1	ENST00000917009.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 11	ENSP00000587068.1
	PDSS1	ENST00000869579.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 10	ENSP00000539638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 8142 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000262 AC: 3 AN: 1143438 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 552210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23136

American (AMR) AF: 0.00 AC: 0 AN: 9628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15488

East Asian (EAS) AF: 0.00 AC: 0 AN: 26446

South Asian (SAS) AF: 0.00 AC: 0 AN: 37132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3078

European-Non Finnish (NFE) AF: 0.00000313 AC: 3 AN: 958042

Other (OTH) AF: 0.00 AC: 0 AN: 45910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0953088), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deafness-encephaloneuropathy-obesity-valvulopathy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.45
Sift	Benign	0.076	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.35		Loss of phosphorylation at S3 (P = 0.1489)
MVP		0.87
MPC		0.53
ClinPred		0.78	D
GERP RS		2.5
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.11
gMVP		0.28
Mutation Taster		=88/12	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: rs1227021452; hg19: chr10-26986659;