9-128322881-T-A

Variant names:

• chr9-128322881-T-A
• NM_016035.5:c.23T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016035.5(COQ4):​c.23T>A​(p.Val8Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.276

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11219567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5	c.23T>A	p.Val8Asp	missense_variant	Exon 1 of 7	ENST00000300452.8	NP_057119.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8	c.23T>A	p.Val8Asp	missense_variant	Exon 1 of 7	1	NM_016035.5	ENSP00000300452.3
COQ4	ENST00000372875.3	c.23T>A	p.Val8Asp	missense_variant	Exon 1 of 4	2		ENSP00000361966.3
COQ4	ENST00000608951.5	c.23T>A	p.Val8Asp	missense_variant	Exon 1 of 3	2		ENSP00000476323.1
COQ4	ENST00000609948.1	c.23T>A	p.Val8Asp	missense_variant	Exon 1 of 2	2		ENSP00000477292.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Uncertain:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 8 of the COQ4 protein (p.Val8Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COQ4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2010333). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.66
DEOGEN2	Benign	0.0093	T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.48	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N;.;.;N
REVEL	Benign	0.016
Sift	Benign	0.070	T;.;.;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		0.089	B;.;.;B
Vest4		0.33
MutPred		0.36		Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);Loss of helix (P = 0.0304);
MVP		0.055
MPC		0.64
ClinPred		0.099	T
GERP RS		0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-131085160;