rs61759492

chr11-63974791-C-Achr11-63974791-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004074.3(COX8A):c.111C>A(p.Ile37=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,601,624 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (39 hom.)
• Consequence: COX8A NM_004074.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.643

Genes affected

COX8A (HGNC:2294): (cytochrome c oxidase subunit 8A) The protein encoded by this gene is the terminal enzyme of the respiratory chain, coupling the transfer of electrons from cytochrome c to molecular oxygen, with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane. In addition to 3 mitochondrially encoded subunits, which perform the catalytic function, the eukaryotic enzyme contains nuclear-encoded smaller subunits, ranging in number from 4 in some organisms to 10 in mammals. It has been proposed that nuclear-encoded subunits may be involved in the modulation of the catalytic function. This gene encodes one of the nuclear-encoded subunits. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-63974791-C-A is Benign according to our data. Variant chr11-63974791-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 709505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.643 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX8A	NM_004074.3	c.111C>A	p.Ile37=	synonymous_variant	1/2	ENST00000314133.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX8A	ENST00000314133.4	c.111C>A	p.Ile37=	synonymous_variant	1/2	1	NM_004074.3	P1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152244 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00760

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00480 AC: 1073 AN: 223360 Hom.: 5 AF XY: 0.00491 AC XY: 598 AN XY: 121672

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0000582

Gnomad SAS exome AF: 0.000211

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00730 AC: 10586 AN: 1449262 Hom.: 39 Cov.: 31 AF XY: 0.00715 AC XY: 5152 AN XY: 720078

Gnomad4 AFR exome AF: 0.000930

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.0000780

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000272

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00862

Gnomad4 OTH exome AF: 0.00582

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152362 Hom.: 4 Cov.: 33 AF XY: 0.00502 AC XY: 374 AN XY: 74492

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.00760

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00368 Hom.: 0

Bravo AF: 0.00449

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	COX8A: BP4, BP7, BS2 -

Mitochondrial complex 4 deficiency, nuclear type 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	6.9
Dann	Benign	0.63

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: rs61759492; hg19: chr11-63742263;