NM_078470.6:c.*3247T>C

Variant names:

• chr10-99711340-A-G
• rs74775778
• NM_078470.6:c.*3247T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_078470.6(COX15):​c.*3247T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 985,142 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (13 hom.)
• Consequence: COX15 NM_078470.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.732
• 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]

ENTPD7 (HGNC:19745): (ectonucleoside triphosphate diphosphohydrolase 7) This gene encodes a purine-converting ectoenzyme which belongs to the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family. The encoded protein hydrolyzes extracellular nucleoside triphosphates (UTP, GTP, and CTP) to nucleoside monophosphates as part of a purinergic signaling pathway. It contains two transmembrane domains at the N- and C-termini and a large, hydrophobic catalytic domain located in between. This gene affects oxidative stress as well as DNA damage and is a mediator of senescence. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00365 (555/152252) while in subpopulation NFE AF = 0.00596 (405/67984). AF 95% confidence interval is 0.00548. There are 2 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.*3247T>C		3_prime_UTR	Exon 9 of 9	NP_510870.1	Q7KZN9-1
	COX15	NM_001372024.1		c.*2466T>C		3_prime_UTR	Exon 9 of 9	NP_001358953.1
	COX15	NM_001372025.1		c.*3247T>C		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.*3247T>C		3_prime_UTR	Exon 9 of 9	ENSP00000016171.6	Q7KZN9-1
	ENSG00000285932	ENST00000649102.1		n.*460+5008T>C		intron	N/A	ENSP00000497114.1	A0A3B3IRX1
	CUTC	ENST00000493385.5	TSL:3	n.116+8667A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00511 AC: 4253 AN: 832890 Hom.: 13 Cov.: 32 AF XY: 0.00503 AC XY: 1933 AN XY: 384594

African (AFR) AF: 0.000190 AC: 3 AN: 15786

American (AMR) AF: 0.00 AC: 0 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00679 AC: 35 AN: 5152

East Asian (EAS) AF: 0.000276 AC: 1 AN: 3628

South Asian (SAS) AF: 0.000791 AC: 13 AN: 16426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.00494 AC: 8 AN: 1618

European-Non Finnish (NFE) AF: 0.00537 AC: 4090 AN: 761734

Other (OTH) AF: 0.00377 AC: 103 AN: 27286

GnomAD4 genome AF: 0.00365 AC: 555 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74448

African (AFR) AF: 0.00130 AC: 54 AN: 41566

American (AMR) AF: 0.00314 AC: 48 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00596 AC: 405 AN: 67984

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00509 Hom.: 0

Bravo AF: 0.00363

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

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

Other links and lift over

dbSNP: rs74775778; hg19: chr10-101471097;