16-85804938-A-T

Variant summary

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

The NM_001861.6(COX4I1):​c.75A>T​(p.Glu25Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

COX4I1
NM_001861.6 missense, splice_region

Scores

1
18
Splicing: ADA: 0.00002160
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.262
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]

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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=0.09549186).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COX4I1NM_001861.6 linkuse as main transcriptc.75A>T p.Glu25Asp 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
COX4I1ENST00000253452.8 linkuse as main transcriptc.75A>T p.Glu25Asp missense_variant, splice_region_variant 3/51 NM_001861.6 ENSP00000253452.2 P13073

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
41
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2024The c.75A>T (p.E25D) alteration is located in exon 3 (coding exon 2) of the COX4I1 gene. This alteration results from a A to T substitution at nucleotide position 75, causing the glutamic acid (E) at amino acid position 25 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
15
DANN
Benign
0.96
DEOGEN2
Benign
0.021
T;T;T;T;T;T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.81
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.77
T;T;.;.;T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.095
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
.;.;N;N;N;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.89
N;N;N;N;N;N
REVEL
Benign
0.014
Sift
Benign
0.43
T;T;T;T;T;T
Sift4G
Benign
0.92
T;T;T;T;T;T
Polyphen
0.057
.;.;B;B;B;.
Vest4
0.18, 0.19, 0.19
MutPred
0.36
Loss of ubiquitination at K29 (P = 0.1191);Loss of ubiquitination at K29 (P = 0.1191);Loss of ubiquitination at K29 (P = 0.1191);Loss of ubiquitination at K29 (P = 0.1191);Loss of ubiquitination at K29 (P = 0.1191);Loss of ubiquitination at K29 (P = 0.1191);
MVP
0.29
MPC
0.074
ClinPred
0.090
T
GERP RS
-0.63
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.024
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000022
dbscSNV1_RF
Benign
0.0060
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.22
Position offset: 3

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.

Other links and lift over

dbSNP: rs957691740; hg19: chr16-85838544; API