10-26697793-C-T

Variant names:

• chr10-26697793-C-T
• rs1834911891
• NM_014317.5:c.82C>T

Variant summary

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

The NM_001321979.2(PDSS1):​c.-512C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,154,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PDSS1 NM_001321979.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11277419).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321979.2. 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.82C>T	p.Arg28Cys	missense	Exon 1 of 12	NP_055132.2	Q5T2R2-1
	PDSS1	NM_001321979.2		c.-512C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001308908.1
	PDSS1	NM_001321978.2		c.82C>T	p.Arg28Cys	missense	Exon 1 of 10	NP_001308907.1	Q5T2R2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS1	ENST00000376215.10	TSL:1 MANE Select	c.82C>T	p.Arg28Cys	missense	Exon 1 of 12	ENSP00000365388.5	Q5T2R2-1
	PDSS1	ENST00000917009.1		c.82C>T	p.Arg28Cys	missense	Exon 1 of 11	ENSP00000587068.1
	PDSS1	ENST00000869579.1		c.82C>T	p.Arg28Cys	missense	Exon 1 of 10	ENSP00000539638.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 4 AN: 1154916 Hom.: 0 Cov.: 30 AF XY: 0.00000179 AC XY: 1 AN XY: 557914

⚠️ 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: 23590

American (AMR) AF: 0.00 AC: 0 AN: 12072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16670

East Asian (EAS) AF: 0.00 AC: 0 AN: 26418

South Asian (SAS) AF: 0.00 AC: 0 AN: 39134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3220

European-Non Finnish (NFE) AF: 0.00000416 AC: 4 AN: 962274

Other (OTH) AF: 0.00 AC: 0 AN: 46664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00376316), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.32		Loss of methylation at R28 (P = 0.0064)
MVP		0.48
MPC		0.64
ClinPred		0.085	T
GERP RS		0.30
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.22
Mutation Taster		=99/1	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: rs1834911891; hg19: chr10-26986722;