Genetic Variant COX15:c.988-8C>T (chr10-99716469-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001372025.1(COX15):c.998C>T(p.Ser333Phe) 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. 7/7 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. S333Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Consequence

COX15
NM_001372025.1 missense

Scores

Splicing: ADA: 0.0001130

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.231

Publications

0 publications found

Variant links:

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]

COX15 links:

ENSG00000285932 (HGNC:):

ENSG00000285932 links:

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]

CUTC links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372025.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX15	NM_078470.6	MANE Select	c.988-8C>T		splice_region intron	N/A	NP_510870.1	Q7KZN9-1
COX15	NM_001372025.1		c.998C>T	p.Ser333Phe	missense	Exon 8 of 9	NP_001358954.1
COX15	NM_001372024.1		c.988-8C>T		splice_region intron	N/A	NP_001358953.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COX15	ENST00000016171.6	TSL:1 MANE Select	c.988-8C>T	splice_region intron	N/A	ENSP00000016171.6	Q7KZN9-1
COX15	ENST00000370483.9	TSL:1	c.988-8C>T	splice_region intron	N/A	ENSP00000359514.5	Q7KZN9-2
ENSG00000285932	ENST00000649102.1		n.*347-8C>T	splice_region intron	N/A	ENSP00000497114.1	A0A3B3IRX1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249572

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

(source)

DANN

Benign

0.83

PhyloP100

-0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over