10-99711938-C-T

Variant names:

• chr10-99711938-C-T
• rs1128642
• NM_078470.6:c.*2649G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_078470.6(COX15):​c.*2649G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 571,726 control chromosomes in the GnomAD database, including 23,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.29 (18219 hom.)
• Consequence: COX15 NM_078470.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-99711938-C-T is Benign according to our data. Variant chr10-99711938-C-T is described in ClinVar as Benign. ClinVar VariationId is 298394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078470.6. 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.*2649G>A		3_prime_UTR	Exon 9 of 9	NP_510870.1	Q7KZN9-1
	COX15	NM_001372024.1		c.*1868G>A		3_prime_UTR	Exon 9 of 9	NP_001358953.1
	COX15	NM_001372025.1		c.*2649G>A		3_prime_UTR	Exon 9 of 9	NP_001358954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX15	ENST00000016171.6	TSL:1 MANE Select	c.*2649G>A		3_prime_UTR	Exon 9 of 9	ENSP00000016171.6	Q7KZN9-1
	COX15	ENST00000370483.9	TSL:1	c.*1476G>A		3_prime_UTR	Exon 9 of 9	ENSP00000359514.5	Q7KZN9-2
	ENSG00000285932	ENST00000649102.1		n.*460+4410G>A		intron	N/A	ENSP00000497114.1	A0A3B3IRX1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41425 AN: 151882 Hom.: 5760 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.290 AC: 121717 AN: 419726 Hom.: 18219 Cov.: 6 AF XY: 0.290 AC XY: 57510 AN XY: 198468

African (AFR) AF: 0.207 AC: 1572 AN: 7578

American (AMR) AF: 0.245 AC: 133 AN: 542

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 463 AN: 2710

East Asian (EAS) AF: 0.281 AC: 506 AN: 1800

South Asian (SAS) AF: 0.182 AC: 1498 AN: 8238

European-Finnish (FIN) AF: 0.340 AC: 53 AN: 156

Middle Eastern (MID) AF: 0.154 AC: 134 AN: 868

European-Non Finnish (NFE) AF: 0.296 AC: 113548 AN: 384190

Other (OTH) AF: 0.279 AC: 3810 AN: 13644

GnomAD4 genome AF: 0.273 AC: 41439 AN: 152000 Hom.: 5759 Cov.: 32 AF XY: 0.274 AC XY: 20328 AN XY: 74278

African (AFR) AF: 0.230 AC: 9548 AN: 41466

American (AMR) AF: 0.238 AC: 3638 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3470

East Asian (EAS) AF: 0.292 AC: 1508 AN: 5172

South Asian (SAS) AF: 0.184 AC: 889 AN: 4822

European-Finnish (FIN) AF: 0.355 AC: 3734 AN: 10530

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20587 AN: 67962

Other (OTH) AF: 0.238 AC: 502 AN: 2108

Alfa AF: 0.205 Hom.: 489

Bravo AF: 0.260

Asia WGS AF: 0.215 AC: 751 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.7
DANN	Benign	0.71
PhyloP100		-0.084
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1128642; hg19: chr10-101471695;