16-85805047-T-C

Variant names:

• chr16-85805047-T-C
• rs2599091
• NM_001861.6:c.184T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001861.6(COX4I1):​c.184T>C​(p.Leu62Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,614,128 control chromosomes in the GnomAD database, including 799,762 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 0.97 (72468 hom., cov: 32)
  • Exomes 𝑓: 1.0 (727294 hom.)
• Consequence: COX4I1 NM_001861.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 18 publications found

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]

COX4I1 Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• mitochondrial complex IV deficiency, nuclear type 16

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX4I1	NM_001861.6	c.184T>C	p.Leu62Leu	synonymous_variant	Exon 3 of 5	ENST00000253452.8	NP_001852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX4I1	ENST00000253452.8	c.184T>C	p.Leu62Leu	synonymous_variant	Exon 3 of 5	1	NM_001861.6	ENSP00000253452.2

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148364 AN: 152198 Hom.: 72418 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.984

GnomAD2 exomes AF: 0.994 AC: 249550 AN: 251138 AF XY: 0.995

Gnomad AFR exome AF: 0.911

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1458052 AN: 1461812 Hom.: 727294 Cov.: 53 AF XY: 0.998 AC XY: 725537 AN XY: 727186

African (AFR) AF: 0.906 AC: 30331 AN: 33474

American (AMR) AF: 0.996 AC: 44546 AN: 44718

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39696

South Asian (SAS) AF: 1.00 AC: 86240 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53373 AN: 53374

Middle Eastern (MID) AF: 0.997 AC: 5745 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1111924 AN: 1111998

Other (OTH) AF: 0.994 AC: 60061 AN: 60394

GnomAD4 genome AF: 0.975 AC: 148472 AN: 152316 Hom.: 72468 Cov.: 32 AF XY: 0.976 AC XY: 72681 AN XY: 74472

African (AFR) AF: 0.911 AC: 37871 AN: 41558

American (AMR) AF: 0.993 AC: 15194 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 0.999 AC: 4829 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68027 AN: 68040

Other (OTH) AF: 0.984 AC: 2081 AN: 2114

Alfa AF: 0.987 Hom.: 33408

Bravo AF: 0.971

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.1
DANN	Benign	0.65
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2599091; hg19: chr16-85838653; COSMIC: COSV108059382; COSMIC: COSV108059382;