NM_014317.5:c.924T>G

Variant names:

• chr10-26735477-T-G
• rs119463988
• NM_014317.5:c.924T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_014317.5(PDSS1):​c.924T>G​(p.Asp308Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D308N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDSS1 NM_014317.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.512
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-26735477-T-G is Pathogenic according to our data. Variant chr10-26735477-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3237.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS1	NM_014317.5	MANE Select	c.924T>G	p.Asp308Glu	missense	Exon 10 of 12	NP_055132.2
	PDSS1	NM_001321979.2		c.414T>G	p.Asp138Glu	missense	Exon 10 of 12	NP_001308908.1
	PDSS1	NM_001321978.2		c.836-7020T>G		intron	N/A	NP_001308907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDSS1	ENST00000376215.10	TSL:1 MANE Select	c.924T>G	p.Asp308Glu	missense	Exon 10 of 12	ENSP00000365388.5
	PDSS1	ENST00000470978.1	TSL:2	n.166T>G		non_coding_transcript_exon	Exon 3 of 5
	PDSS1	ENST00000491711.5	TSL:5	n.330T>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000435695.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness-encephaloneuropathy-obesity-valvulopathy syndrome Pathogenic:1 Other:1

Mar 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.46	N
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		-0.51
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of stability (P = 0.1346)
MVP		0.86
MPC		1.3
ClinPred		1.0	D
GERP RS		-5.7
Varity_R		0.95
gMVP		0.89
Mutation Taster		=33/67	disease causing (ClinVar)

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: rs119463988; hg19: chr10-27024406;