15-74937941-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_004255.4(COX5A):c.74C>G(p.Ser25Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00349 in 1,232,312 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 9 hom. )

Consequence

COX5A
NM_004255.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.95

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045795143).

BP6

Variant 15-74937941-G-C is Benign according to our data. Variant chr15-74937941-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 783061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX5A	NM_004255.4 linkuse as main transcript	c.74C>G	p.Ser25Cys	missense_variant	1/5	ENST00000322347.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX5A	ENST00000322347.11 linkuse as main transcript	c.74C>G	p.Ser25Cys	missense_variant	1/5	1	NM_004255.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00404

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00316

AC:

AN:

2532

Hom.:

AF XY:

0.00349

AC XY:

AN XY:

1434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00645

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00368

AC:

3973

AN:

1080088

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

1920

AN XY:

510258

show subpopulations

Gnomad4 AFR exome

AF:

0.000743

Gnomad4 AMR exome

AF:

0.00131

Gnomad4 ASJ exome

AF:

0.000910

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00162

Gnomad4 NFE exome

AF:

0.00412

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00214

AC:

326

AN:

152224

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00404

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00455

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000611

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

COX5A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T;.;T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.015

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0046

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.;.;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.91

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.053

T;T;D;D;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.24

B;.;.;.;B

Vest4

0.11

MVP

0.23

MPC

0.25

ClinPred

0.086

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.15

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over