rs35213511

chr9-128332931-G-Achr9-128332931-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016035.5(COQ4):c.614G>A(p.Arg205Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,613,948 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.97

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.017378509).
• BP6: Variant 9-128332931-G-A is Benign according to our data. Variant chr9-128332931-G-A is described in ClinVar as [Benign]. Clinvar id is 382106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332931-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00418 (636/152312) while in subpopulation AFR AF= 0.0147 (613/41562). AF 95% confidence interval is 0.0138. There are 5 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ4	NM_016035.5	c.614G>A	p.Arg205Gln	missense_variant	6/7	ENST00000300452.8
COQ4	XM_017014792.2	c.*84G>A		3_prime_UTR_variant	4/4
COQ4	NM_001305942.2	c.*3-543G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ4	ENST00000300452.8	c.614G>A	p.Arg205Gln	missense_variant	6/7	1	NM_016035.5	P1
COQ4	ENST00000461102.1	n.2520G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 632 AN: 152194 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00105 AC: 265 AN: 251482 Hom.: 1 AF XY: 0.000780 AC XY: 106 AN XY: 135914

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1461636 Hom.: 4 Cov.: 31 AF XY: 0.000338 AC XY: 246 AN XY: 727172

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00393 AC XY: 293 AN XY: 74474

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000493 Hom.: 0

Bravo AF: 0.00454

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	COQ4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	- -

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

COQ4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	12
Dann	Benign	0.96
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.24
Sift	Benign	0.060	T
Sift4G	Benign	0.062	T
Polyphen		0.17	B
Vest4		0.21
MVP		0.49
MPC		0.46
ClinPred		0.082	T
GERP RS		2.3
Varity_R		0.18
gMVP		0.65

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: rs35213511; hg19: chr9-131095210;