rs4885

Positions:

• chr16-85805091-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001861.6(COX4I1):​c.228T>C​(p.Asp76=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.30

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 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/exons	MANE	Protein	UniProt
COX4I1	NM_001861.6	c.228T>C	p.Asp76=	synonymous_variant	3/5	ENST00000253452.8	NP_001852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I1	ENST00000253452.8	c.228T>C	p.Asp76=	synonymous_variant	3/5	1	NM_001861.6	ENSP00000253452	P1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1793 AN: 152016 Hom.: 41 Cov.: 32

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.: 13 AF XY: 0.00333 AC XY: 447 AN XY: 134326

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.: 33 Cov.: 34 AF XY: 0.00183 AC XY: 1328 AN XY: 726312

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.: 44 Cov.: 32 AF XY: 0.0112 AC XY: 836 AN XY: 74394

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.: 8

Bravo AF: 0.0144

Asia WGS AF: 0.00520 AC: 18 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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Mitochondrial complex 4 deficiency, nuclear type 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

COX4I1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

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

Other links and lift over

dbSNP: rs4885; hg19: chr16-85838697;