rs1554796655

Variant names:

• chr9-128322923-C-CG
• rs1554796655
• NM_016035.5:c.67dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016035.5(COQ4):​c.67dupG​(p.Ala23GlyfsTer8) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ4 NM_016035.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.318
• Publications: 0 publications found

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]

TRUB2 (HGNC:17170): (TruB pseudouridine synthase family member 2) Pseudouridine is an abundant component of rRNAs and tRNAs and is enzymatically generated by isomerization of uridine by pseudouridine synthase (Zucchini et al., 2003 [PubMed 12736709]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 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 37 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 VariationId is 476186.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016035.5. 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
	COQ4	NM_016035.5	MANE Select	c.67dupG	p.Ala23GlyfsTer8	frameshift splice_region	Exon 1 of 7	NP_057119.3	Q9Y3A0-1
	COQ4	NM_001305942.2		c.67dupG	p.Ala23GlyfsTer8	frameshift splice_region	Exon 1 of 4	NP_001292871.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ4	ENST00000300452.8	TSL:1 MANE Select	c.67dupG	p.Ala23GlyfsTer8	frameshift splice_region	Exon 1 of 7	ENSP00000300452.3	Q9Y3A0-1
	COQ4	ENST00000926106.1		c.67dupG	p.Ala23GlyfsTer8	frameshift splice_region	Exon 1 of 8	ENSP00000596165.1
	COQ4	ENST00000926105.1		c.67dupG	p.Ala23GlyfsTer8	frameshift splice_region	Exon 1 of 8	ENSP00000596164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554796655; hg19: chr9-131085202;