10-99713459-AAA-CAG

Variant names:

• chr10-99713459-AAA-CAG
• ENST00000370483.9:c.1120_1122delTTTinsCTG
• COX15 p.Phe374Leu

Variant summary

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

The NM_004376.7(COX15):​c.1120_1122delTTTinsCTG​(p.Phe374Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COX15 NM_004376.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912
• Publications: 0 publications found

Genes affected

COX15 (HGNC:2263): (cytochrome c oxidase assembly homolog COX15) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be essential for the biogenesis of COX formation and may function in the hydroxylation of heme O, according to the yeast mutant studies. This protein is predicted to contain 5 transmembrane domains localized in the mitochondrial inner membrane. Alternative splicing of this gene generates two transcript variants diverging in the 3' region. [provided by RefSeq, Jul 2008]

ENSG00000285932 (HGNC:):

CUTC (HGNC:24271): (cutC copper transporter) Members of the CUT family of copper transporters are associated with copper homeostasis and are involved in the uptake, storage, delivery, and efflux of copper (Gupta et al., 1995 [PubMed 7635807]; Li et al., 2005 [PubMed 16182249]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004376.7. 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
	COX15	NM_078470.6	MANE Select	c.*1126_*1128delTTTinsCTG		3_prime_UTR	Exon 9 of 9	NP_510870.1	Q7KZN9-1
	COX15	NM_004376.7		c.1120_1122delTTTinsCTG	p.Phe374Leu	missense	N/A	NP_004367.2
	COX15	NM_001372024.1		c.*345_*347delTTTinsCTG		3_prime_UTR	Exon 9 of 9	NP_001358953.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX15	ENST00000370483.9	TSL:1	c.1120_1122delTTTinsCTG	p.Phe374Leu	missense	N/A	ENSP00000359514.5	Q7KZN9-2
	COX15	ENST00000016171.6	TSL:1 MANE Select	c.*1126_*1128delTTTinsCTG		3_prime_UTR	Exon 9 of 9	ENSP00000016171.6	Q7KZN9-1
	ENSG00000285932	ENST00000649102.1		n.*460+2887_*460+2889delTTTinsCTG		intron	N/A	ENSP00000497114.1	A0A3B3IRX1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91

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: chr10-101473216;