rs1554796655

Positions:

• chr9-128322923-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016035.5(COQ4):​c.67dup​(p.Ala23GlyfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ4 NM_016035.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.318

Genes affected

COQ4 (HGNC:19693): (coenzyme Q4) This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 60 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-128322923-C-CG is Pathogenic according to our data. Variant chr9-128322923-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 476186.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ4	NM_016035.5	c.67dup	p.Ala23GlyfsTer8	frameshift_variant	1/7	ENST00000300452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ4	ENST00000300452.8	c.67dup	p.Ala23GlyfsTer8	frameshift_variant	1/7	1	NM_016035.5	P1
COQ4	ENST00000372875.3	c.67dup	p.Ala23GlyfsTer8	frameshift_variant	1/4	2
COQ4	ENST00000608951.5	c.67dup	p.Ala23GlyfsTer8	frameshift_variant	1/3	2
COQ4	ENST00000609948.1	c.67dup	p.Ala23GlyfsTer8	frameshift_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2018

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in COQ4 are known to be pathogenic (PMID: 25658047, 26185144). This sequence change inserts 1 nucleotide in exon 1 of the COQ4 mRNA (c.67dupG), causing a frameshift at codon 23. This creates a premature translational stop signal (p.Ala23Glyfs*8) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554796655; hg19: chr9-131085202;