chr16-85801213-C-T

Position:

• chr16-85801213-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001861.6(COX4I1):​c.8C>T​(p.Ala3Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,340 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COX4I1 NM_001861.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

Genes affected

COX4I1 (HGNC:2265): (cytochrome c oxidase subunit 4I1) 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 and 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 IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3180037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I1	NM_001861.6	c.8C>T	p.Ala3Val	missense_variant	2/5	ENST00000253452.8	NP_001852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I1	ENST00000253452.8	c.8C>T	p.Ala3Val	missense_variant	2/5	1	NM_001861.6	ENSP00000253452.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455340 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722866

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D;.;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	2.9	.;.;M;M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.78	.;.;P;P;P;.
Vest4		0.75, 0.75, 0.65, 0.76
MutPred		0.27		Loss of methylation at R5 (P = 0.071);Loss of methylation at R5 (P = 0.071);Loss of methylation at R5 (P = 0.071);Loss of methylation at R5 (P = 0.071);Loss of methylation at R5 (P = 0.071);Loss of methylation at R5 (P = 0.071);
MVP		0.49
MPC		0.23
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr16-85834819;