Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001861.6(COX4I1):c.228T>C(p.Asp76Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,612,068 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 33 hom. )

Consequence

COX4I1
NM_001861.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.30

Publications

9 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

COX4I1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 16-85805091-T-C is Benign according to our data. Variant chr16-85805091-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 780190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.3 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1805/152134) while in subpopulation AFR AF = 0.0371 (1540/41484). AF 95% confidence interval is 0.0356. There are 44 homozygotes in GnomAd4. There are 836 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

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
COX4I1	NM_001861.6	MANE Select	c.228T>C	p.Asp76Asp	synonymous	Exon 3 of 5	NP_001852.1
COX4I1	NM_001318802.2		c.2T>C	p.Met1?	start_lost	Exon 3 of 5	NP_001305731.1
COX4I1	NM_001318786.3		c.228T>C	p.Asp76Asp	synonymous	Exon 3 of 5	NP_001305715.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COX4I1	ENST00000253452.8	TSL:1 MANE Select	c.228T>C	p.Asp76Asp	synonymous	Exon 3 of 5	ENSP00000253452.2
COX4I1	ENST00000561569.5	TSL:2	c.228T>C	p.Asp76Asp	synonymous	Exon 3 of 5	ENSP00000457015.1
COX4I1	ENST00000562336.5	TSL:5	c.228T>C	p.Asp76Asp	synonymous	Exon 3 of 5	ENSP00000457513.1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1793

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0369

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0168

GnomAD2 exomes

AF:

0.00402

AC:

995

AN:

247376

AF XY:

0.00333

show subpopulations

Gnomad AFR exome

AF:

0.0374

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000848

Gnomad OTH exome

AF:

0.00534

GnomAD4 exome

AF:

0.00195

AC:

2849

AN:

1459934

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1328

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.0393

AC:

1312

AN:

33376

American (AMR)

AF:

0.00421

AC:

186

AN:

44230

Ashkenazi Jewish (ASJ)

AF:

0.0145

AC:

378

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000174

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000496

AC:

551

AN:

1111328

Other (OTH)

AF:

0.00561

AC:

338

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

132

264

395

527

659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0119

AC:

1805

AN:

152134

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

836

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0371

AC:

1540

AN:

41484

American (AMR)

AF:

0.00824

AC:

126

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68000

Other (OTH)

AF:

0.0166

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00669

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

COX4I1-related disorder (1)

Mitochondrial complex IV deficiency, nuclear type 16 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.2

(source)

DANN

Benign

0.64

PhyloP100

-1.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs4885

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over