rs770654508

Variant names:

• chr16-19072015-G-A
• rs770654508
• NM_016138.5:c.161G>A
• COQ7 p.Arg54Gln

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PP3_Strong PP5

The NM_016138.5(COQ7):​c.161G>A​(p.Arg54Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002768318: "This variant has strong functional evidence supporting abnormal protein function. Low ubiquinone level and a severe reduction in COQ7 protein level were shown in the skin fibroblasts from an affected individual who is homozygous for this variant (PMID:35782625). Similar findings were shown in the fibroblasts from this proband (MRFF-funded mito MDT project). In addition, a higher increase in the respiratory chain complex II+III activity was detected in this proband’s fibroblasts when supplemented with a CoQ analog, compared to the control cell lines (MRFF-funded mito MDT project). Functional studies using a yeast model suggest this variant is hypomorphic (PMID:37392700)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: COQ7 NM_016138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 7.73
• Publications: 5 publications found

Genes affected

COQ7 (HGNC:2244): (coenzyme Q7, hydroxylase) The protein encoded by this gene is similar to a mitochondrial di-iron containing hydroxylase in Saccharomyces cerevisiae that is involved with ubiquinone biosynthesis. Mutations in the yeast gene lead to slower development and longer life span. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

COQ7-DT (HGNC:55362): (COQ7 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002768318: "This variant has strong functional evidence supporting abnormal protein function. Low ubiquinone level and a severe reduction in COQ7 protein level were shown in the skin fibroblasts from an affected individual who is homozygous for this variant (PMID: 35782625). Similar findings were shown in the fibroblasts from this proband (MRFF-funded mito MDT project). In addition, a higher increase in the respiratory chain complex II+III activity was detected in this proband’s fibroblasts when supplemented with a CoQ analog, compared to the control cell lines (MRFF-funded mito MDT project). Functional studies using a yeast model suggest this variant is hypomorphic (PMID: 37392700)."; SCV006583039: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 35782625, 37392700).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 16-19072015-G-A is Pathogenic according to our data. Variant chr16-19072015-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587428.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016138.5. 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
	COQ7	NM_016138.5	MANE Select	c.161G>A	p.Arg54Gln	missense	Exon 2 of 6	NP_057222.2
	COQ7	NM_001370489.1		c.119G>A	p.Arg40Gln	missense	Exon 2 of 6	NP_001357418.1
	COQ7	NM_001370490.1		c.161G>A	p.Arg54Gln	missense	Exon 2 of 5	NP_001357419.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ7	ENST00000321998.10	TSL:1 MANE Select	c.161G>A	p.Arg54Gln	missense	Exon 2 of 6	ENSP00000322316.5	Q99807-1
	COQ7	ENST00000544894.6	TSL:1	c.47G>A	p.Arg16Gln	missense	Exon 2 of 6	ENSP00000442923.2	Q99807-2
	COQ7	ENST00000568985.5	TSL:2	c.161G>A	p.Arg54Gln	missense	Exon 2 of 7	ENSP00000456734.1	Q99807-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251488 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Primary coenzyme Q10 deficiency 8 (4)
3	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 9 (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.92
Mutation Taster		=52/48	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

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

Other links and lift over

dbSNP: rs770654508;

hg19: chr16-19083337;