10-26697790-G-T

Variant names:

• chr10-26697790-G-T
• NM_014317.5:c.79G>T

Variant summary

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

The NM_001321979.2(PDSS1):​c.-515G>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 0.00000259 in 1,159,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: PDSS1 NM_001321979.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.913
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.79G>T	p.Gly27Cys	missense	Exon 1 of 12	NP_055132.2	Q5T2R2-1
	PDSS1	NM_001321979.2		c.-515G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001308908.1
	PDSS1	NM_001321978.2		c.79G>T	p.Gly27Cys	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.79G>T	p.Gly27Cys	missense	Exon 1 of 12	ENSP00000365388.5	Q5T2R2-1
	PDSS1	ENST00000917009.1		c.79G>T	p.Gly27Cys	missense	Exon 1 of 11	ENSP00000587068.1
	PDSS1	ENST00000869579.1		c.79G>T	p.Gly27Cys	missense	Exon 1 of 10	ENSP00000539638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000259 AC: 3 AN: 1159590 Hom.: 0 Cov.: 30 AF XY: 0.00000356 AC XY: 2 AN XY: 561024

African (AFR) AF: 0.00 AC: 0 AN: 23654

American (AMR) AF: 0.00 AC: 0 AN: 11982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16564

East Asian (EAS) AF: 0.00 AC: 0 AN: 26548

South Asian (SAS) AF: 0.00 AC: 0 AN: 39926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 965662

Other (OTH) AF: 0.00 AC: 0 AN: 46900

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.0040
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.91
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.86
MPC		1.4
ClinPred		0.91	D
GERP RS		4.7
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.39
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

hg19: chr10-26986719;