chr10-99713461-A-C

Variant names:

• chr10-99713461-A-C
• rs2231687
• ENST00000370483.9:c.1120T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004376.7(COX15):​c.1120T>G​(p.Phe374Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. 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. F374L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COX15 NM_004376.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 33 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04944694).

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.*1126T>G		3_prime_UTR	Exon 9 of 9	NP_510870.1	Q7KZN9-1
	COX15	NM_004376.7		c.1120T>G	p.Phe374Val	missense	Exon 9 of 9	NP_004367.2
	COX15	NM_001372024.1		c.*345T>G		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.1120T>G	p.Phe374Val	missense	Exon 9 of 9	ENSP00000359514.5	Q7KZN9-2
	COX15	ENST00000016171.6	TSL:1 MANE Select	c.*1126T>G		3_prime_UTR	Exon 9 of 9	ENSP00000016171.6	Q7KZN9-1
	ENSG00000285932	ENST00000649102.1		n.*460+2887T>G		intron	N/A	ENSP00000497114.1	A0A3B3IRX1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.5
DANN	Benign	0.87
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.011
PROVEAN	Benign	1.6	N
REVEL	Benign	0.022
Sift	Benign	0.80	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.21
MutPred		0.51		Gain of sheet (P = 0.0477)
MVP		0.23
ClinPred		0.047	T
GERP RS		0.95
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2231687; hg19: chr10-101473218;