15-74920016-A-G

Variant names:

• chr15-74920016-A-G
• rs1133322
• NM_004255.4:c.*436T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004255.4(COX5A):​c.*436T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 254,372 control chromosomes in the GnomAD database, including 25,874 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (13524 hom., cov: 32)
  • Exomes 𝑓: 0.47 (12350 hom.)
• Consequence: COX5A NM_004255.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162
• Publications: 25 publications found

Genes affected

COX5A (HGNC:2267): (cytochrome c oxidase subunit 5A) Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Va of the human mitochondrial respiratory chain enzyme. A pseudogene COX5AP1 has been found in chromosome 14q22. [provided by RefSeq, Jul 2008]

COX5A Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex IV deficiency, nuclear type 20

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX5A	NM_004255.4	c.*436T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000322347.11	NP_004246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX5A	ENST00000322347.11	c.*436T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_004255.4	ENSP00000317780.6

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56918 AN: 151956 Hom.: 13524 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.465 AC: 47581 AN: 102298 Hom.: 12350 Cov.: 0 AF XY: 0.445 AC XY: 23778 AN XY: 53426

African (AFR) AF: 0.119 AC: 230 AN: 1928

American (AMR) AF: 0.434 AC: 703 AN: 1620

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1593 AN: 3404

East Asian (EAS) AF: 0.178 AC: 603 AN: 3396

South Asian (SAS) AF: 0.198 AC: 2318 AN: 11712

European-Finnish (FIN) AF: 0.439 AC: 2353 AN: 5358

Middle Eastern (MID) AF: 0.358 AC: 181 AN: 506

European-Non Finnish (NFE) AF: 0.539 AC: 36622 AN: 67948

Other (OTH) AF: 0.463 AC: 2978 AN: 6426

GnomAD4 genome AF: 0.374 AC: 56924 AN: 152074 Hom.: 13524 Cov.: 32 AF XY: 0.365 AC XY: 27138 AN XY: 74350

African (AFR) AF: 0.104 AC: 4331 AN: 41548

American (AMR) AF: 0.437 AC: 6662 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1606 AN: 3468

East Asian (EAS) AF: 0.180 AC: 929 AN: 5166

South Asian (SAS) AF: 0.180 AC: 869 AN: 4822

European-Finnish (FIN) AF: 0.431 AC: 4551 AN: 10568

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36642 AN: 67970

Other (OTH) AF: 0.392 AC: 825 AN: 2106

Alfa AF: 0.475 Hom.: 52670

Bravo AF: 0.371

Asia WGS AF: 0.178 AC: 623 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1133322; hg19: chr15-75212357; COSMIC: COSV59279977; COSMIC: COSV59279977;