Genetic Variant COX5A:c.*436T>C (chr15-74920016-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.162

Publications

25 publications found

Variant links:

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

COX5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX5A	NM_004255.4	MANE Select	c.*436T>C		3_prime_UTR	Exon 5 of 5	NP_004246.2	P20674

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX5A	ENST00000322347.11	TSL:1 MANE Select	c.*436T>C		3_prime_UTR	Exon 5 of 5	ENSP00000317780.6	P20674
	COX5A	ENST00000873797.1		c.*436T>C		3_prime_UTR	Exon 5 of 5	ENSP00000543856.1

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

56918

AN:

151956

Hom.:

13524

Cov.:

show subpopulations

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.:

AF XY:

0.445

AC XY:

23778

AN XY:

53426

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1146

2292

3437

4583

5729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.374

AC:

56924

AN:

152074

Hom.:

13524

Cov.:

AF XY:

0.365

AC XY:

27138

AN XY:

74350

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1543

3086

4630

6173

7716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over