rs587776904

Variant names:

• chr12-50120100-G-A
• rs587776904
• NM_032901.4:c.57G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The ENST00000550487.6(COX14):​c.57G>A​(p.Met19Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COX14 ENST00000550487.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.52
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 10

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000272368 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.059703 (below the threshold of 3.09). Trascript score misZ: 0.15848 (below the threshold of 3.09). GenCC associations: The gene is linked to cytochrome-c oxidase deficiency disease, mitochondrial disease, mitochondrial complex IV deficiency, nuclear type 10.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 12-50120100-G-A is Pathogenic according to our data. Variant chr12-50120100-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31196.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550487.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX14	NM_032901.4	MANE Select	c.57G>A	p.Met19Ile	missense	Exon 2 of 2	NP_116290.1
	COX14	NM_001257133.2		c.57G>A	p.Met19Ile	missense	Exon 3 of 3	NP_001244062.1
	COX14	NM_001257134.2		c.57G>A	p.Met19Ile	missense	Exon 2 of 2	NP_001244063.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX14	ENST00000550487.6	TSL:1 MANE Select	c.57G>A	p.Met19Ile	missense	Exon 2 of 2	ENSP00000446524.1
	COX14	ENST00000317943.6	TSL:2	c.57G>A	p.Met19Ile	missense	Exon 3 of 3	ENSP00000326052.2
	COX14	ENST00000548985.1	TSL:2	c.57G>A	p.Met19Ile	missense	Exon 2 of 2	ENSP00000447776.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.16	T
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.89	P
Vest4		0.96
MutPred		0.30		Loss of helix (P = 0.0558)
MVP		0.72
MPC		0.54
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.53
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776904; hg19: chr12-50513883;