chr15-74929205-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_004255.4(COX5A):c.128A>G(p.His43Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
COX5A
NM_004255.4 missense
NM_004255.4 missense
Scores
8
10
Clinical Significance
Conservation
PhyloP100: 7.51
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 Uncertain_significance. Variant got 2 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;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23840266).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COX5A | NM_004255.4 | c.128A>G | p.His43Arg | missense_variant | 2/5 | ENST00000322347.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COX5A | ENST00000322347.11 | c.128A>G | p.His43Arg | missense_variant | 2/5 | 1 | NM_004255.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152162Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251462Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135906
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GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461546Hom.: 0 Cov.: 29 AF XY: 0.0000426 AC XY: 31AN XY: 727124
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 27, 2023 | The c.128A>G (p.H43R) alteration is located in exon 2 (coding exon 2) of the COX5A gene. This alteration results from a A to G substitution at nucleotide position 128, causing the histidine (H) at amino acid position 43 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;T;T;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Benign
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
B;.;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at