12-50120110-ACT-TCA

Variant names:

• chr12-50120110-ACT-TCA
• NM_032901.4:c.67_69delACTinsTCA
• COX14 p.Thr23Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_032901.4(COX14):​c.67_69delACTinsTCA​(p.Thr23Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T23I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COX14 NM_032901.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.02
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• 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 mitochondrial complex IV deficiency, nuclear type 10, mitochondrial disease, cytochrome-c oxidase deficiency disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032901.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX14	NM_032901.4	MANE Select	c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	NP_116290.1	Q96I36
	COX14	NM_001257133.2		c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	NP_001244062.1	Q96I36
	COX14	NM_001257134.2		c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	NP_001244063.1	Q96I36

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX14	ENST00000550487.6	TSL:1 MANE Select	c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	ENSP00000446524.1	Q96I36
	COX14	ENST00000317943.6	TSL:2	c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	ENSP00000326052.2	Q96I36
	COX14	ENST00000548985.1	TSL:2	c.67_69delACTinsTCA	p.Thr23Ser	missense	N/A	ENSP00000447776.1	Q96I36

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-50513893;