14-73950133-G-A

Variant names:

• chr14-73950133-G-A
• rs17094161
• ENST00000554341.6:n.41G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_182480.3(COQ6):​c.41G>A​(p.Trp14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,598,314 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (73 hom.)
• Consequence: COQ6 NM_182480.3 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.97

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

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.969 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• BP6: Variant 14-73950133-G-A is Benign according to our data. Variant chr14-73950133-G-A is described in ClinVar as [Benign]. Clinvar id is 136986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73950133-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM161B	NM_152445.3	c.-107C>T		upstream_gene_variant		ENST00000286544.5	NP_689658.3
COQ6	NM_182476.3	c.-200G>A		upstream_gene_variant		ENST00000334571.7	NP_872282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM161B	ENST00000286544.5	c.-107C>T		upstream_gene_variant		1	NM_152445.3	ENSP00000286544.4
COQ6	ENST00000334571.7	c.-200G>A		upstream_gene_variant		1	NM_182476.3	ENSP00000333946.2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2354 AN: 152242 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00402 AC: 904 AN: 224968 Hom.: 19 AF XY: 0.00316 AC XY: 393 AN XY: 124426

Gnomad AFR exome AF: 0.0555

Gnomad AMR exome AF: 0.00302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000172

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00183 AC: 2646 AN: 1445954 Hom.: 73 Cov.: 32 AF XY: 0.00164 AC XY: 1181 AN XY: 719758

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.00334

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000329

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.0155 AC: 2363 AN: 152360 Hom.: 63 Cov.: 33 AF XY: 0.0146 AC XY: 1090 AN XY: 74512

Gnomad4 AFR AF: 0.0534

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00853 Hom.: 13

Bravo AF: 0.0176

ExAC AF: 0.00471 AC: 568

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

COQ6-related disorder Benign:1

Jul 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial steroid-resistant nephrotic syndrome with sensorineural deafness Benign:1

May 07, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.2
DANN	Uncertain	0.98
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.020
Sift	Uncertain	0.015	D
Vest4		0.16
MVP		0.27
MPC		0.065
ClinPred		0.048	T
GERP RS		3.3

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

LitVar

Other links and lift over

dbSNP: rs17094161; hg19: chr14-74416836;