rs1555358729

Variant names:

• chr14-73961349-CG-C
• rs1555358729
• NM_182476.3:c.1069delG

Variant summary

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

The NM_182476.3(COQ6):​c.1069delG​(p.Val357SerfsTer47) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COQ6 NM_182476.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.59
• Publications: 0 publications found

Genes affected

COQ6 (HGNC:20233): (coenzyme Q6, monooxygenase) The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. Knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis. Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2012]

ENTPD5 (HGNC:3367): (ectonucleoside triphosphate diphosphohydrolase 5 (inactive)) The protein encoded by this gene is similar to E-type nucleotidases (NTPases)/ecto-ATPase/apyrases. NTPases, such as CD39, mediate catabolism of extracellular nucleotides. ENTPD5 contains 4 apyrase-conserved regions which is characteristic of NTPases. [provided by RefSeq, Jan 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-73961349-CG-C is Pathogenic according to our data. Variant chr14-73961349-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 434818.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182476.3. 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
	COQ6	NM_182476.3	MANE Select	c.1069delG	p.Val357SerfsTer47	frameshift	Exon 9 of 12	NP_872282.1	Q9Y2Z9-1
	COQ6	NM_001425255.1		c.1069delG	p.Val357SerfsTer47	frameshift	Exon 9 of 11	NP_001412184.1
	COQ6	NM_182480.3		c.994delG	p.Val332SerfsTer47	frameshift	Exon 9 of 12	NP_872286.2	Q9Y2Z9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	ENST00000334571.7	TSL:1 MANE Select	c.1069delG	p.Val357SerfsTer47	frameshift	Exon 9 of 12	ENSP00000333946.2	Q9Y2Z9-1
	COQ6	ENST00000554341.6	TSL:1	n.*674delG		non_coding_transcript_exon	Exon 8 of 11	ENSP00000450736.2	G3V2L5
	COQ6	ENST00000554341.6	TSL:1	n.*674delG		3_prime_UTR	Exon 8 of 11	ENSP00000450736.2	G3V2L5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial steroid-resistant nephrotic syndrome with sensorineural deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=0/200	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555358729;

hg19: chr14-74428052;