14-73950333-A-T

Variant names:

• chr14-73950333-A-T
• rs753591978
• NM_182476.3:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001425257.1(COQ6):​c.-106A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COQ6 NM_001425257.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

Genes affected

COQ6 (HGNC:20233): (coenzyme Q6, monooxygenase) The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. Knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis. Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2012]

FAM161B (HGNC:19854): (FAM161 centrosomal protein B) Predicted to be involved in cilium organization. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425257.1. 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
	COQ6	NM_182476.3	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 12	NP_872282.1	Q9Y2Z9-1
	COQ6	NM_001425257.1		c.-106A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001412186.1
	COQ6	NM_001425260.1		c.-268A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001412189.1	A0A0D9SFJ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	ENST00000334571.7	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 12	ENSP00000333946.2	Q9Y2Z9-1
	COQ6	ENST00000554193.5	TSL:1	n.24A>T		non_coding_transcript_exon	Exon 1 of 4
	COQ6	ENST00000556300.6	TSL:1	n.35A>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398358 Hom.: 0 Cov.: 32 AF XY: 0.00000289 AC XY: 2 AN XY: 691012

African (AFR) AF: 0.00 AC: 0 AN: 31998

American (AMR) AF: 0.00 AC: 0 AN: 36456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 36252

South Asian (SAS) AF: 0.00 AC: 0 AN: 80104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1082790

Other (OTH) AF: 0.00 AC: 0 AN: 58222

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.70
MutPred		1.0		Gain of stability (P = 0.0205)
MVP		0.25
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.53	Under-expression
Varity_R		0.97
gMVP		0.51
Mutation Taster		=23/177	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs753591978; hg19: chr14-74417036;