rs765791496

Positions:

• chr9-128323089-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_016035.5(COQ4):​c.144G>T​(p.Gln48His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,459,730 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (size 234) in uniprot entity COQ4_HUMAN there are 48 pathogenic changes around while only 10 benign (83%) in NM_016035.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ4	NM_016035.5	c.144G>T	p.Gln48His	missense_variant	2/7	ENST00000300452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ4	ENST00000300452.8	c.144G>T	p.Gln48His	missense_variant	2/7	1	NM_016035.5	P1
COQ4	ENST00000372875.3	c.144G>T	p.Gln48His	missense_variant	2/4	2
COQ4	ENST00000608951.5	c.144G>T	p.Gln48His	missense_variant	2/3	2
COQ4	ENST00000609948.1	c.144G>T	p.Gln48His	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000167 AC: 4 AN: 239160 Hom.: 0 AF XY: 0.0000305 AC XY: 4 AN XY: 131288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1459730 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 726230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000711 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000249 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COQ4-related disease. This variant is present in population databases (rs765791496, ExAC 0.002%). This sequence change replaces glutamine with histidine at codon 48 of the COQ4 protein (p.Gln48His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.6	H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D;.;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.86
MutPred		0.74		Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);Loss of catalytic residue at Q48 (P = 0.0071);
MVP		0.60
MPC		1.2
ClinPred		0.99	D
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs765791496; hg19: chr9-131085368;