9-128332233-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_016035.5(COQ4):c.483G>C(p.Glu161Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,613,374 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E161G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 85 hom. )

Consequence

COQ4
NM_016035.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.884

Publications

18 publications found

Variant links:

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]

COQ4 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

COQ4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_016035.5

BP4

Computational evidence support a benign effect (MetaRNN=0.018062353).

BP6

Variant 9-128332233-G-C is Benign according to our data. Variant chr9-128332233-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00555 (845/152292) while in subpopulation SAS AF = 0.0104 (50/4830). AF 95% confidence interval is 0.00807. There are 6 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COQ4	NM_016035.5 link	c.483G>C	p.Glu161Asp	missense_variant	Exon 5 of 7	ENST00000300452.8	NP_057119.3
COQ4	XM_047423449.1 link	c.*83G>C		3_prime_UTR_variant	Exon 4 of 4		XP_047279405.1
COQ4	NM_001305942.2 link	c.*3-1241G>C		intron_variant	Intron 3 of 3		NP_001292871.2
COQ4	XM_017014792.2 link	c.*3-617G>C		intron_variant	Intron 3 of 3		XP_016870281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8 link	c.483G>C	p.Glu161Asp	missense_variant	Exon 5 of 7	1	NM_016035.5	ENSP00000300452.3
COQ4	ENST00000461102.1 link	n.1822G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00809

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00629

AC:

1568

AN:

249250

AF XY:

0.00641

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00279

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00862

Gnomad OTH exome

AF:

0.00755

GnomAD4 exome

AF:

0.00838

AC:

12239

AN:

1461082

Hom.:

Cov.:

AF XY:

0.00849

AC XY:

6168

AN XY:

726752

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33464

American (AMR)

AF:

0.00347

AC:

155

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

296

AN:

26112

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.0106

AC:

915

AN:

86008

European-Finnish (FIN)

AF:

0.00227

AC:

121

AN:

53388

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00919

AC:

10219

AN:

1111776

Other (OTH)

AF:

0.00780

AC:

471

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

633

1265

1898

2530

3163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

392

784

1176

1568

1960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00555

AC:

845

AN:

152292

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41558

American (AMR)

AF:

0.00575

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00809

AC:

550

AN:

68018

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00812

Hom.:

Bravo

AF:

0.00603

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00647

AC:

785

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00837

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COQ4: BS1, BS2

not specified

Benign:1

Apr 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.49

MutationAssessor

Pathogenic

3.8

PhyloP100

0.88

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.45

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.039

Vest4

0.90

ClinPred

0.058

GERP RS

2.8

Varity_R

0.67

gMVP

0.75

Mutation Taster

=39/61

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over