rs8500

chr14-73961742-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182476.3(COQ6):c.1216G>A(p.Val406Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,496 control chromosomes in the GnomAD database, including 177,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13309 hom., cov: 31)
  • Exomes 𝑓: 0.47 (164525 hom.)
• Consequence: COQ6 NM_182476.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.04

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]

ENTPD5 (HGNC:3367): (ectonucleoside triphosphate diphosphohydrolase 5 (inactive)) The protein encoded by this gene is similar to E-type nucleotidases (NTPases)/ecto-ATPase/apyrases. NTPases, such as CD39, mediate catabolism of extracellular nucleotides. ENTPD5 contains 4 apyrase-conserved regions which is characteristic of NTPases. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6542964E-4).
• BP6: Variant 14-73961742-G-A is Benign according to our data. Variant chr14-73961742-G-A is described in ClinVar as [Benign]. Clinvar id is 128834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73961742-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ6	NM_182476.3	c.1216G>A	p.Val406Met	missense_variant	11/12	ENST00000334571.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ6	ENST00000334571.7	c.1216G>A	p.Val406Met	missense_variant	11/12	1	NM_182476.3	P1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60761 AN: 151870 Hom.: 13317 Cov.: 31

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.439 AC: 110366 AN: 251462 Hom.: 25798 AF XY: 0.450 AC XY: 61152 AN XY: 135908

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.188

Gnomad SAS exome AF: 0.504

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.481

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.470 AC: 686380 AN: 1461508 Hom.: 164525 Cov.: 48 AF XY: 0.472 AC XY: 343231 AN XY: 727086

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.504

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.400 AC: 60765 AN: 151988 Hom.: 13309 Cov.: 31 AF XY: 0.405 AC XY: 30062 AN XY: 74294

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.423

Alfa AF: 0.462 Hom.: 43116

Bravo AF: 0.378

TwinsUK AF: 0.473 AC: 1754

ALSPAC AF: 0.479 AC: 1845

ESP6500AA AF: 0.213 AC: 940

ESP6500EA AF: 0.472 AC: 4061

ExAC AF: 0.435 AC: 52763

Asia WGS AF: 0.389 AC: 1354 AN: 3478

EpiCase AF: 0.482

EpiControl AF: 0.485

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2013	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Benign	0.75
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.32	T;T;T
MetaRNN	Benign	0.00087	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.15	N;.;N
REVEL	Benign	0.070
Sift	Benign	0.55	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.089
MPC		0.29
ClinPred		0.0059	T
GERP RS		4.1
Varity_R		0.041
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8500; hg19: chr14-74428445; COSMIC: COSV53178775; COSMIC: COSV53178775;