14-73950161-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The ENST00000554341.6(COQ6):c.69A>G(p.Pro23=) variant causes a synonymous, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,585,412 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: COQ6 ENST00000554341.6 synonymous, NMD_transcript
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.189

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003535539).
• BP6: Variant 14-73950161-A-G is Benign according to our data. Variant chr14-73950161-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1187588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.189 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00161 (246/152346) while in subpopulation AFR AF= 0.00575 (239/41578). AF 95% confidence interval is 0.00515. There are 2 homozygotes in gnomad4. There are 136 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ6	NM_182480.3	c.69A>G	p.Pro23=	synonymous_variant	1/12
COQ6	XM_047431424.1	c.69A>G	p.Pro23=	synonymous_variant	1/11
COQ6	XM_011536809.4	c.-23A>G		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ6	ENST00000554341.6	c.69A>G	p.Pro23=	synonymous_variant, NMD_transcript_variant	1/11	1
FAM161B	ENST00000651776.1	c.55T>C	p.Trp19Arg	missense_variant	1/9
COQ6	ENST00000394026.8	c.69A>G	p.Pro23=	synonymous_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000425 AC: 86 AN: 202438 Hom.: 0 AF XY: 0.000241 AC XY: 27 AN XY: 112158

Gnomad AFR exome AF: 0.00691

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 228 AN: 1433066 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 80 AN XY: 712474

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.000241

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.00161 AC: 246 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74494

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000470 Hom.: 0

ExAC AF: 0.000414 AC: 49

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COQ6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	3.4
Dann	Benign	0.57
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.014
Sift	Pathogenic	0.0	D
Vest4		0.13
MutPred		0.18		Gain of methylation at W19 (P = 0.0062);
MVP		0.055
MPC		0.11
ClinPred		0.055	T
GERP RS		-2.8

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: rs186482754; hg19: chr14-74416864;