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GeneBe

15-74926839-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_004255.4(COX5A):c.266T>G(p.Ile89Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

COX5A
NM_004255.4 missense

Scores

11
5
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.84
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a chain Cytochrome c oxidase subunit 5A, mitochondrial (size 108) in uniprot entity COX5A_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004255.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 15-74926839-A-C is Pathogenic according to our data. Variant chr15-74926839-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3028911.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-74926839-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COX5ANM_004255.4 linkuse as main transcriptc.266T>G p.Ile89Ser missense_variant 3/5 ENST00000322347.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COX5AENST00000322347.11 linkuse as main transcriptc.266T>G p.Ile89Ser missense_variant 3/51 NM_004255.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 20 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 07, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
Cadd
Pathogenic
29
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;D;D;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Benign
0.038
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D
MetaSVM
Uncertain
0.015
D
MutationAssessor
Uncertain
2.3
M;.;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-5.2
D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;.;.;D
Vest4
0.91
MutPred
0.79
Gain of disorder (P = 0.0116);.;Gain of disorder (P = 0.0116);.;Gain of disorder (P = 0.0116);
MVP
0.84
MPC
0.92
ClinPred
0.99
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75219180; API