16-85805103-G-C

Position:

chr16-85805103-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001861.6(COX4I1):c.240G>C(p.Glu80Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,611,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

COX4I1
NM_001861.6 missense, splice_region

Scores

Splicing: ADA: 0.0002310

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

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:

COX4I1 (HGNC:):

COX4I1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14340407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I1	NM_001861.6 linkuse as main transcript	c.240G>C	p.Glu80Asp	missense_variant, splice_region_variant	3/5	ENST00000253452.8	NP_001852.1	P13073

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I1	ENST00000253452.8 linkuse as main transcript	c.240G>C	p.Glu80Asp	missense_variant, splice_region_variant	3/5	1	NM_001861.6	ENSP00000253452.2		P13073

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000247

AC:

AN:

246754

Hom.:

AF XY:

0.000201

AC XY:

AN XY:

134124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000341

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000528

AC:

770

AN:

1459384

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

381

AN XY:

726078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000498

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000630

Gnomad4 OTH exome

AF:

0.000763

GnomAD4 genome

AF:

0.000250

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000373

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

COX4I1: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

T;T;T;T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.83

T;.;.;T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.3

.;L;L;L;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N;N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.20

T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.0

.;B;B;B;.;.

Vest4

0.31

MutPred

0.42

Loss of ubiquitination at K85 (P = 0.0768);Loss of ubiquitination at K85 (P = 0.0768);Loss of ubiquitination at K85 (P = 0.0768);Loss of ubiquitination at K85 (P = 0.0768);.;Loss of ubiquitination at K85 (P = 0.0768);

MVP

0.47

MPC

0.065

ClinPred

0.051

GERP RS

0.018

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.058

SpliceAI score (max)

0.14

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