16-19067665-A-C

Variant names:

• chr16-19067665-A-C
• NM_016138.5:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_016138.5(COQ7):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ7 NM_016138.5 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.38

Genes affected

COQ7 (HGNC:2244): (coenzyme Q7, hydroxylase) The protein encoded by this gene is similar to a mitochondrial di-iron containing hydroxylase in Saccharomyces cerevisiae that is involved with ubiquinone biosynthesis. Mutations in the yeast gene lead to slower development and longer life span. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

COQ7-DT (HGNC:55362): (COQ7 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 39 codons. Genomic position: 19071969. Lost 0.176 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-19067665-A-C is Pathogenic according to our data. Variant chr16-19067665-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573010.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ7	NM_016138.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6	ENST00000321998.10	NP_057222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ7	ENST00000321998.10	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6	1	NM_016138.5	ENSP00000322316.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary coenzyme Q10 deficiency 8 Pathogenic:1

May 06, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COQ7 c.1A>C (p.?) is a start loss variant. The resultant protein is described as p.? to denote that whether the loss prevents all protein translation or causes abnormal protein formation from an alternate start codon is unknown. While the c.1A>C variant has not been reported in the peer-reviewed literature, two other variants leading to a similar protein change c.3G>T (p.?) and c.1A>G (p.?) have been reported in a homozygous state in six individuals from two families affected by distal hereditary motor neuropathy (PMID: 36454683, 37077559). The c.1A>C variant has not been observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.1A>C (p.?) variant is classified as likely pathogenic for primary coenzyme Q10 deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	0.033
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.50	N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.52	P;P
Vest4		0.90
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0059);Loss of catalytic residue at M1 (P = 0.0059);
MVP		0.35
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.41

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: chr16-19078987;