10-99713461-A-G

Position:

• chr10-99713461-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004376.7(COX15):​c.1120T>C​(p.Phe374Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,613,432 control chromosomes in the GnomAD database, including 609,113 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54015 hom., cov: 31)
  • Exomes 𝑓: 0.87 (555098 hom.)
• Consequence: COX15 NM_004376.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0110

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.523721E-7).
• BP6: Variant 10-99713461-A-G is Benign according to our data. Variant chr10-99713461-A-G is described in ClinVar as [Benign]. Clinvar id is 128836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-99713461-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX15	NM_078470.6	c.*1126T>C		3_prime_UTR_variant	9/9	ENST00000016171.6	NP_510870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX15	ENST00000370483.9	c.1120T>C	p.Phe374Leu	missense_variant	9/9	1		ENSP00000359514.5
COX15	ENST00000016171	c.*1126T>C		3_prime_UTR_variant	9/9	1	NM_078470.6	ENSP00000016171.6
ENSG00000285932	ENST00000649102.1	n.*460+2887T>C		intron_variant				ENSP00000497114.1
CUTC	ENST00000493385.5	n.117-9457A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127802 AN: 151960 Hom.: 53984 Cov.: 31

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.878

Gnomad OTH AF: 0.852

GnomAD3 exomes AF: 0.864 AC: 214132 AN: 247958 Hom.: 92694 AF XY: 0.867 AC XY: 116460 AN XY: 134306

Gnomad AFR exome AF: 0.759

Gnomad AMR exome AF: 0.898

Gnomad ASJ exome AF: 0.836

Gnomad EAS exome AF: 0.777

Gnomad SAS exome AF: 0.877

Gnomad FIN exome AF: 0.890

Gnomad NFE exome AF: 0.876

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.871 AC: 1272771 AN: 1461354 Hom.: 555098 Cov.: 53 AF XY: 0.872 AC XY: 633758 AN XY: 726996

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.896

Gnomad4 ASJ exome AF: 0.833

Gnomad4 EAS exome AF: 0.789

Gnomad4 SAS exome AF: 0.880

Gnomad4 FIN exome AF: 0.887

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.862

GnomAD4 genome AF: 0.841 AC: 127891 AN: 152078 Hom.: 54015 Cov.: 31 AF XY: 0.842 AC XY: 62576 AN XY: 74356

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.873

Gnomad4 ASJ AF: 0.831

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.873

Gnomad4 FIN AF: 0.889

Gnomad4 NFE AF: 0.878

Gnomad4 OTH AF: 0.848

Alfa AF: 0.868 Hom.: 141272

Bravo AF: 0.836

TwinsUK AF: 0.872 AC: 3232

ALSPAC AF: 0.877 AC: 3381

ESP6500AA AF: 0.760 AC: 3348

ESP6500EA AF: 0.873 AC: 7510

ExAC AF: 0.860 AC: 104350

Asia WGS AF: 0.818 AC: 2849 AN: 3478

EpiCase AF: 0.880

EpiControl AF: 0.875

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant summary: COX15 c.1120T>C (p.Phe374Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.86 in 273702 control chromosomes (gnomAD), suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 690-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in COX15 causing Leigh Syndrome phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1120T>C in individuals affected with Leigh Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.87
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.52		Loss of sheet (P = 0.0357);
ClinPred		0.0018	T
GERP RS		0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2231687; hg19: chr10-101473218;