rs34043652

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.424G>A(p.Ala142Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00548 in 1,582,382 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A142A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 82 hom. )

Consequence

COQ4
NM_016035.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.85

Publications

10 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_016035.5

BP4

Computational evidence support a benign effect (MetaRNN=0.007909).

BP6

Variant 9-128332174-G-A is Benign according to our data. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128332174-G-A is described in CliVar as Benign. Clinvar id is 383917.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 = 0.0037 (564/152312) while in subpopulation SAS AF = 0.0334 (161/4820). AF 95% confidence interval is 0.0292. There are 5 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5 link	c.424G>A	p.Ala142Thr	missense_variant	Exon 5 of 7	ENST00000300452.8	NP_057119.3	Q9Y3A0-1
COQ4	XM_047423449.1 link	c.*24G>A		3_prime_UTR_variant	Exon 4 of 4		XP_047279405.1
COQ4	NM_001305942.2 link	c.*3-1300G>A		intron_variant	Intron 3 of 3		NP_001292871.2	A0A024R890
COQ4	XM_017014792.2 link	c.*3-676G>A		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.424G>A	p.Ala142Thr	missense_variant	Exon 5 of 7	1	NM_016035.5	ENSP00000300452.3		Q9Y3A0-1
COQ4	ENST00000461102.1 link	n.1763G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00372

AC:

566

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0336

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00691

AC:

1386

AN:

200580

AF XY:

0.00862

show subpopulations

Gnomad AFR exome

AF:

0.000904

Gnomad AMR exome

AF:

0.00155

Gnomad ASJ exome

AF:

0.00177

Gnomad EAS exome

AF:

0.000134

Gnomad FIN exome

AF:

0.000456

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.00388

GnomAD4 exome

AF:

0.00567

AC:

8109

AN:

1430070

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

4655

AN XY:

708620

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

32774

American (AMR)

AF:

0.00164

AC:

AN:

39684

Ashkenazi Jewish (ASJ)

AF:

0.00212

AC:

AN:

25474

East Asian (EAS)

AF:

0.0000527

AC:

AN:

37922

South Asian (SAS)

AF:

0.0331

AC:

2718

AN:

82020

European-Finnish (FIN)

AF:

0.000371

AC:

AN:

51236

Middle Eastern (MID)

AF:

0.0148

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00438

AC:

4803

AN:

1096022

Other (OTH)

AF:

0.00545

AC:

323

AN:

59212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

412

824

1236

1648

2060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00370

AC:

564

AN:

152312

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

310

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41564

American (AMR)

AF:

0.00242

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0334

AC:

161

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00453

AC:

308

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

114

143

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:

0.00445

Hom.:

Bravo

AF:

0.00331

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00621

AC:

751

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 20, 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 30, 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

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

PhyloP100

4.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

REVEL

Benign

0.16

Sift

Benign

0.45

Sift4G

Benign

0.51

Polyphen

0.98

Vest4

0.23

MVP

0.59

MPC

0.61

ClinPred

0.033

GERP RS

5.8

Varity_R

0.054

gMVP

0.44

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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