rs11557187

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.081 ( 701 hom., cov: 32)

Exomes 𝑓: 0.066 ( 4700 hom. )

Consequence

COX4I1
NM_001861.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.02

Publications

25 publications found

Variant links:

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
mitochondrial disease
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

COX4I1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001861.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX4I1	NM_001861.6	MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	NP_001852.1	P13073
COX4I1	NM_001318786.3		c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	NP_001305715.1	P13073
COX4I1	NM_001318788.2		c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	NP_001305717.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX4I1	ENST00000253452.8	TSL:1 MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	ENSP00000253452.2	P13073
COX4I1	ENST00000924851.1		c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	ENSP00000594910.1
COX4I1	ENST00000906734.1		c.7G>A	p.Ala3Thr	missense	Exon 2 of 5	ENSP00000576793.1

Frequencies

GnomAD3 genomes

AF:

0.0813

AC:

12362

AN:

152070

Hom.:

696

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0943

AC:

23712

AN:

251376

AF XY:

0.0894

show subpopulations

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 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.:

AF XY:

0.0656

AC XY:

47287

AN XY:

721304

show subpopulations

African (AFR)

AF:

0.0963

AC:

3214

AN:

33366

American (AMR)

AF:

0.140

AC:

6261

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.0663

AC:

1726

AN:

26026

East Asian (EAS)

AF:

0.290

AC:

11444

AN:

39404

South Asian (SAS)

AF:

0.0959

AC:

8237

AN:

85896

European-Finnish (FIN)

AF:

0.0467

AC:

2490

AN:

53300

Middle Eastern (MID)

AF:

0.0352

AC:

202

AN:

5746

European-Non Finnish (NFE)

AF:

0.0522

AC:

57638

AN:

1104368

Other (OTH)

AF:

0.0697

AC:

4187

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

3981

7962

11944

15925

19906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2414

4828

7242

9656

12070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0814

AC:

12387

AN:

152188

Hom.:

701

Cov.:

AF XY:

0.0828

AC XY:

6160

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.101

AC:

4200

AN:

41514

American (AMR)

AF:

0.0911

AC:

1392

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0632

AC:

219

AN:

3466

East Asian (EAS)

AF:

0.306

AC:

1584

AN:

5170

South Asian (SAS)

AF:

0.0943

AC:

455

AN:

4826

European-Finnish (FIN)

AF:

0.0447

AC:

473

AN:

10590

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0564

AC:

3836

AN:

68020

Other (OTH)

AF:

0.0668

AC:

141

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

564

1127

1691

2254

2818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0644

Hom.:

1489

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

COX4I1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

3.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.072

Sift

Benign

0.046

Sift4G

Benign

0.080

Polyphen

0.18

Vest4

0.36

MPC

0.073

ClinPred

0.032

GERP RS

3.4

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.75

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over