rs4885

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBS1BS2

The NM_001318802.2(COX4I1):c.2T>C(p.Met1?) variant causes a start lost 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_001318802.2 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.30

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 34 codons. Genomic position: 85805768. Lost 0.280 part of the original CDS.

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX4I1	NM_001861.6 link	c.228T>C	p.Asp76Asp	synonymous_variant	Exon 3 of 5	ENST00000253452.8	NP_001852.1	P13073

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX4I1	ENST00000253452.8 link	c.228T>C	p.Asp76Asp	synonymous_variant	Exon 3 of 5	1	NM_001861.6	ENSP00000253452.2		P13073

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

GnomAD3 exomes

AF:

0.00402

AC:

995

AN:

247376

Hom.:

AF XY:

0.00333

AC XY:

447

AN XY:

134326

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 SAS exome

AF:

0.000132

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

Gnomad4 AFR exome

AF:

0.0393

Gnomad4 AMR exome

AF:

0.00421

Gnomad4 ASJ exome

AF:

0.0145

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.00561

GnomAD4 genome

AF:

0.0119

AC:

1805

AN:

152134

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

836

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0371

Gnomad4 AMR

AF:

0.00824

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00697

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex 4 deficiency, nuclear type 16

Benign:1

Feb 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COX4I1-related disorder

Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.2

DANN

Benign

0.64

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over