10-99713461-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000370483.9(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. 11/15 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
ENST00000370483.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0110

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 128836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370483.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COX15	NM_078470.6	MANE Select	c.*1126T>C		3_prime_UTR	Exon 9 of 9	NP_510870.1
COX15	NM_004376.7		c.1120T>C	p.Phe374Leu	missense	Exon 9 of 9	NP_004367.2
COX15	NR_164009.1		n.2199T>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COX15	ENST00000370483.9	TSL:1	c.1120T>C	p.Phe374Leu	missense	Exon 9 of 9	ENSP00000359514.5
COX15	ENST00000016171.6	TSL:1 MANE Select	c.*1126T>C		3_prime_UTR	Exon 9 of 9	ENSP00000016171.6
ENSG00000285932	ENST00000649102.1		n.*460+2887T>C		intron	N/A	ENSP00000497114.1

Frequencies

GnomAD3 genomes

AF:

0.841

AC:

127802

AN:

151960

Hom.:

53984

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.864

AC:

214132

AN:

247958

AF XY:

0.867

show subpopulations

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 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.:

AF XY:

0.872

AC XY:

633758

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.755

AC:

25285

AN:

33476

American (AMR)

AF:

0.896

AC:

40061

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.833

AC:

21771

AN:

26134

East Asian (EAS)

AF:

0.789

AC:

31307

AN:

39672

South Asian (SAS)

AF:

0.880

AC:

75883

AN:

86252

European-Finnish (FIN)

AF:

0.887

AC:

47199

AN:

53182

Middle Eastern (MID)

AF:

0.906

AC:

5224

AN:

5766

European-Non Finnish (NFE)

AF:

0.876

AC:

974022

AN:

1111804

Other (OTH)

AF:

0.862

AC:

52019

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8871

17742

26613

35484

44355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21300

42600

63900

85200

106500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.841

AC:

127891

AN:

152078

Hom.:

54015

Cov.:

AF XY:

0.842

AC XY:

62576

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.759

AC:

31452

AN:

41426

American (AMR)

AF:

0.873

AC:

13347

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.831

AC:

2882

AN:

3470

East Asian (EAS)

AF:

0.786

AC:

4055

AN:

5160

South Asian (SAS)

AF:

0.873

AC:

4208

AN:

4820

European-Finnish (FIN)

AF:

0.889

AC:

9413

AN:

10586

Middle Eastern (MID)

AF:

0.918

AC:

268

AN:

292

European-Non Finnish (NFE)

AF:

0.878

AC:

59732

AN:

68020

Other (OTH)

AF:

0.848

AC:

1792

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1005

2011

3016

4022

5027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.865

Hom.:

190639

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.8

(source)

DANN

Benign

0.87

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.28

MetaRNN

Benign

8.5e-7

MetaSVM

Benign

-1.1

PhyloP100

0.011

PROVEAN

Benign

0.62

REVEL

Benign

0.047

Sift

Benign

1.0

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.037

MutPred

0.52

Loss of sheet (P = 0.0357)

ClinPred

0.0018

GERP RS

0.95

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over