chr9-128332174-G-A

Variant names:

• chr9-128332174-G-A
• rs34043652
• NM_016035.5:c.424G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 4.85
• Publications: 10 publications found

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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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 ClinVar as Benign. ClinVar VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016035.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ4	NM_016035.5	MANE Select	c.424G>A	p.Ala142Thr	missense	Exon 5 of 7	NP_057119.3
	COQ4	NM_001305942.2		c.*3-1300G>A		intron	N/A	NP_001292871.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ4	ENST00000300452.8	TSL:1 MANE Select	c.424G>A	p.Ala142Thr	missense	Exon 5 of 7	ENSP00000300452.3
	COQ4	ENST00000926106.1		c.484G>A	p.Ala162Thr	missense	Exon 6 of 8	ENSP00000596165.1
	COQ4	ENST00000926105.1		c.475G>A	p.Ala159Thr	missense	Exon 6 of 8	ENSP00000596164.1

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

GnomAD2 exomes AF: 0.00691 AC: 1386 AN: 200580 AF XY: 0.00862

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

African (AFR) AF: 0.00122 AC: 40 AN: 32774

American (AMR) AF: 0.00164 AC: 65 AN: 39684

Ashkenazi Jewish (ASJ) AF: 0.00212 AC: 54 AN: 25474

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37922

South Asian (SAS) AF: 0.0331 AC: 2718 AN: 82020

European-Finnish (FIN) AF: 0.000371 AC: 19 AN: 51236

Middle Eastern (MID) AF: 0.0148 AC: 85 AN: 5726

European-Non Finnish (NFE) AF: 0.00438 AC: 4803 AN: 1096022

Other (OTH) AF: 0.00545 AC: 323 AN: 59212

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

African (AFR) AF: 0.000770 AC: 32 AN: 41564

American (AMR) AF: 0.00242 AC: 37 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00445 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.8
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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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