12-50120164-C-T

Position:

chr12-50120164-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032901.4(COX14):c.121C>T(p.Arg41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

COX14
NM_032901.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.06

Variant links:

Genes affected

COX14 (HGNC:28216): (cytochrome c oxidase assembly factor COX14) This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

COX14 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COX14	NM_032901.4 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	2/2	ENST00000550487.6
COX14	NM_001257133.2 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	3/3
COX14	NM_001257134.2 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	2/2
COX14	XM_047429769.1 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX14	ENST00000550487.6 linkuse as main transcript	c.121C>T	p.Arg41Cys	missense_variant	2/2	1	NM_032901.4	P1
	ENST00000548468.2 linkuse as main transcript	n.105+7863C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251424

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000923

AC:

135

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000151

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	p.Arg41Cys (CGC>TGC): c.121 C>T in exon 2 of the COX14 gene (NM_032901.3). The R41C missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a positively charged Arginine residue is replaced by an uncharged Cysteine residue and the introduction of a Cysteine residue could affect disulfide bonds in the COX14 protein. This change occurs at a conserved position in the COX14 protein. In-silico analyses are not consistent in their predictions of whether or not R41C is damaging to the COX14 protein. Therefore, based on the currently available information, it is unclear whether R41C is a disease-causing mutation or a rare benign variant. The variant is found in LAPDH-MITOP,MITONUC-MITOP panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 41 of the COX14 protein (p.Arg41Cys). This variant is present in population databases (rs148220171, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COX14-related conditions. ClinVar contains an entry for this variant (Variation ID: 214249). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.121C>T (p.R41C) alteration is located in exon 2 (coding exon 1) of the COX14 gene. This alteration results from a C to T substitution at nucleotide position 121, causing the arginine (R) at amino acid position 41 to be replaced by a cysteine (C). 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

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.16

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.5

D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.58

MVP

0.74

MPC

0.53

ClinPred

0.33

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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