12-50120046-G-A

Position:

• chr12-50120046-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_032901.4(COX14):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COX14 NM_032901.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.01

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]

ENSG00000272368 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX14	NM_032901.4	c.3G>A	p.Met1?	start_lost	2/2	ENST00000550487.6	NP_116290.1
COX14	NM_001257133.2	c.3G>A	p.Met1?	start_lost	3/3		NP_001244062.1
COX14	NM_001257134.2	c.3G>A	p.Met1?	start_lost	2/2		NP_001244063.1
COX14	XM_047429769.1	c.3G>A	p.Met1?	start_lost	3/3		XP_047285725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX14	ENST00000550487.6	c.3G>A	p.Met1?	start_lost	2/2	1	NM_032901.4	ENSP00000446524.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251426 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2022	Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. This sequence change affects the initiator methionine of the COX14 mRNA. The next in-frame methionine is located at codon 19. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COX14-related conditions. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 18, 2023	PM2_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;.;.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.21	D
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.92
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0086);Gain of catalytic residue at M1 (P = 0.0086);Gain of catalytic residue at M1 (P = 0.0086);Gain of catalytic residue at M1 (P = 0.0086);
MVP		0.71
ClinPred		0.94	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1209388617; hg19: chr12-50513829;