14-73958235-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182476.3(COQ6):c.570T>C(p.His190=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,646 control chromosomes in the GnomAD database, including 127,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8877 hom., cov: 32)
  • Exomes 𝑓: 0.39 (118799 hom.)
• Consequence: COQ6 NM_182476.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0490

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-73958235-T-C is Benign according to our data. Variant chr14-73958235-T-C is described in ClinVar as [Benign]. Clinvar id is 128835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73958235-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ6	NM_182476.3	c.570T>C	p.His190=	synonymous_variant	5/12	ENST00000334571.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ6	ENST00000334571.7	c.570T>C	p.His190=	synonymous_variant	5/12	1	NM_182476.3	P1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45949 AN: 152028 Hom.: 8872 Cov.: 32

Gnomad AFR AF: 0.0838

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.309

GnomAD3 exomes AF: 0.334 AC: 84090 AN: 251464 Hom.: 16445 AF XY: 0.338 AC XY: 45884 AN XY: 135908

Gnomad AFR exome AF: 0.0771

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.409

Gnomad EAS exome AF: 0.0322

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.392 AC: 572598 AN: 1461500 Hom.: 118799 Cov.: 38 AF XY: 0.388 AC XY: 282334 AN XY: 727070

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.0567

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.426

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.302 AC: 45954 AN: 152146 Hom.: 8877 Cov.: 32 AF XY: 0.303 AC XY: 22562 AN XY: 74378

Gnomad4 AFR AF: 0.0835

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.0452

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.312

Alfa AF: 0.388 Hom.: 19615

Bravo AF: 0.281

Asia WGS AF: 0.182 AC: 634 AN: 3478

EpiCase AF: 0.409

EpiControl AF: 0.409

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

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
BayesDel_noAF	Benign	-0.50
Cadd	Benign	6.3
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3180946; hg19: chr14-74424938; COSMIC: COSV53178766; COSMIC: COSV53178766;