9-128323094-G-C

Position:

• chr9-128323094-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_016035.5(COQ4):​c.149G>C​(p.Gly50Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,611,922 control chromosomes in the GnomAD database, including 804,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 1.0 (75679 hom., cov: 36)
  • Exomes 𝑓: 1.0 (728657 hom.)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0510

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 27 pathogenic changes around while only 3 benign (90%) in NM_016035.5
• BP4: Computational evidence support a benign effect (MetaRNN=6.3978564E-7).
• BP6: Variant 9-128323094-G-C is Benign according to our data. Variant chr9-128323094-G-C is described in ClinVar as [Benign]. Clinvar id is 1167959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ4	NM_016035.5	c.149G>C	p.Gly50Ala	missense_variant	2/7	ENST00000300452.8	NP_057119.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8	c.149G>C	p.Gly50Ala	missense_variant	2/7	1	NM_016035.5	ENSP00000300452.3
COQ4	ENST00000372875.3	c.149G>C	p.Gly50Ala	missense_variant	2/4	2		ENSP00000361966.3
COQ4	ENST00000608951.5	c.149G>C	p.Gly50Ala	missense_variant	2/3	2		ENSP00000476323.1
COQ4	ENST00000609948.1	c.149G>C	p.Gly50Ala	missense_variant	2/2	2		ENSP00000477292.1

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151751 AN: 152270 Hom.: 75620 Cov.: 36

Gnomad AFR AF: 0.989

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.995

GnomAD3 exomes AF: 0.999 AC: 238516 AN: 238778 Hom.: 119128 AF XY: 0.999 AC XY: 131034 AN XY: 131146

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1458423 AN: 1459534 Hom.: 728657 Cov.: 63 AF XY: 0.999 AC XY: 725638 AN XY: 726156

Gnomad4 AFR exome AF: 0.989

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.997 AC: 151869 AN: 152388 Hom.: 75679 Cov.: 36 AF XY: 0.997 AC XY: 74260 AN XY: 74518

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.995

Alfa AF: 0.854 Hom.: 19522

Bravo AF: 0.996

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.992 AC: 4180

ESP6500EA AF: 1.00 AC: 8319

ExAC AF: 0.999 AC: 119418

Asia WGS AF: 1.00 AC: 3478 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.3
DANN	Benign	0.80
DEOGEN2	Benign	0.070	T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.060	T;T;T;T
MetaRNN	Benign	6.4e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.9	N;.;.;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;.;.;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.032
MPC		0.42
ClinPred		0.00038	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.051
gMVP		0.53

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: rs3003601; hg19: chr9-131085373;