rs34043652

chr9-128332174-G-A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.85

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 ClinVar 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 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.424G>A	p.Ala142Thr	missense_variant	5/7	ENST00000300452.8
COQ4	XM_047423449.1	c.*24G>A		3_prime_UTR_variant	4/4
COQ4	NM_001305942.2	c.*3-1300G>A		intron_variant
COQ4	XM_017014792.2	c.*3-676G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ4	ENST00000300452.8	c.424G>A	p.Ala142Thr	missense_variant	5/7	1	NM_016035.5	P1
COQ4	ENST00000461102.1	n.1763G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152194 Hom.: 5 Cov.: 32

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

GnomAD3 exomes AF: 0.00691 AC: 1386 AN: 200580 Hom.: 22 AF XY: 0.00862 AC XY: 929 AN XY: 107720

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 SAS exome AF: 0.0331

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.: 82 Cov.: 31 AF XY: 0.00657 AC XY: 4655 AN XY: 708620

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.0000527

Gnomad4 SAS exome AF: 0.0331

Gnomad4 FIN exome AF: 0.000371

Gnomad4 NFE exome AF: 0.00438

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00416 AC XY: 310 AN XY: 74476

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00446 Hom.: 3

Bravo AF: 0.00331

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00621 AC: 751

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.45	T
Sift4G	Benign	0.51	T
Polyphen		0.98	D
Vest4		0.23
MVP		0.59
MPC		0.61
ClinPred		0.033	T
GERP RS		5.8
Varity_R		0.054
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs34043652; hg19: chr9-131094453; COSMIC: COSV105824182;