12-120522315-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032314.4(COQ5):c.251A>G(p.Asp84Gly) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ5 NM_032314.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

COQ5 (HGNC:28722): (coenzyme Q5, methyltransferase) Enables 2-octaprenyl-6-methoxy-1,4-benzoquinone methylase activity. Involved in methylation and ubiquinone biosynthetic process. Located in mitochondrial matrix. Part of protein-containing complex. Colocalizes with mitochondrial inner membrane. Implicated in primary coenzyme Q10 deficiency 9. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ5	NM_032314.4	c.251A>G	p.Asp84Gly	missense_variant	2/7	ENST00000288532.11
COQ5	XM_006719639.3	c.8A>G	p.Asp3Gly	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ5	ENST00000288532.11	c.251A>G	p.Asp84Gly	missense_variant	2/7	1	NM_032314.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.251A>G (p.D84G) alteration is located in exon 2 (coding exon 2) of the COQ5 gene. This alteration results from a A to G substitution at nucleotide position 251, causing the aspartic acid (D) at amino acid position 84 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.96
MutPred		0.76		Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);.;.;.;
MVP		0.90
MPC		0.75
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-120960118;