rs11557187

Positions:

• chr16-85801212-G-A
• chr16-85801212-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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]

COX4I1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
COX4I1	NM_001861.6	c.7G>A	p.Ala3Thr	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.7G>A	p.Ala3Thr	missense_variant	2/5	1	NM_001861.6	ENSP00000253452.2

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: no assertion criteria provided

Submissions by phenotype

COX4I1-related disorder Benign:1

Benign, no assertion criteria provided

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
MutationAssessor	Benign	1.3	.;.;L;L;L;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;N;N;N;N;N
REVEL	Benign	0.072
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;