rs11557187

chr16-85801212-G-Achr16-85801212-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001861.6(COX4I1):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 1,604,934 control chromosomes in the GnomAD database, including 5,401 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.081 (701 hom., cov: 32)
  • Exomes 𝑓: 0.066 (4700 hom.)
• Consequence: COX4I1 NM_001861.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001401186).
• BP6: Variant 16-85801212-G-A is Benign according to our data. Variant chr16-85801212-G-A is described in ClinVar as [Benign]. Clinvar id is 3060855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX4I1	NM_001861.6	c.7G>A	p.Ala3Thr	missense_variant	2/5	ENST00000253452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX4I1	ENST00000253452.8	c.7G>A	p.Ala3Thr	missense_variant	2/5	1	NM_001861.6	P1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12362 AN: 152070 Hom.: 696 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.0632

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0943 AC: 23712 AN: 251376 Hom.: 1783 AF XY: 0.0894 AC XY: 12140 AN XY: 135856

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.316

Gnomad SAS exome AF: 0.0946

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0657 AC: 95399 AN: 1452746 Hom.: 4700 Cov.: 30 AF XY: 0.0656 AC XY: 47287 AN XY: 721304

Gnomad4 AFR exome AF: 0.0963

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0663

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.0959

Gnomad4 FIN exome AF: 0.0467

Gnomad4 NFE exome AF: 0.0522

Gnomad4 OTH exome AF: 0.0697

GnomAD4 genome AF: 0.0814 AC: 12387 AN: 152188 Hom.: 701 Cov.: 32 AF XY: 0.0828 AC XY: 6160 AN XY: 74386

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.0632

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.0943

Gnomad4 FIN AF: 0.0447

Gnomad4 NFE AF: 0.0564

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0635 Hom.: 711

Bravo AF: 0.0881

TwinsUK AF: 0.0512 AC: 190

ALSPAC AF: 0.0537 AC: 207

ESP6500AA AF: 0.104 AC: 459

ESP6500EA AF: 0.0560 AC: 482

ExAC AF: 0.0906 AC: 11003

Asia WGS AF: 0.178 AC: 619 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

COX4I1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as 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	0.31
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T;T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T;T;.;.;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.000068	P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;N;N;N;N;N
Sift	Benign	0.046	D;T;T;T;T;T
Sift4G	Benign	0.080	T;T;T;T;T;T
Polyphen		0.18	.;.;B;B;B;.
Vest4		0.36, 0.35, 0.12, 0.39
MPC		0.073
ClinPred		0.032	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.75

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

Other links and lift over

dbSNP: rs11557187; hg19: chr16-85834818; COSMIC: COSV53665976; COSMIC: COSV53665976;