17-14069543-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001303.4(COX10):c.-63C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,599,678 control chromosomes in the GnomAD database, including 1,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (77 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1006 hom.)
• Consequence: COX10 NM_001303.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.17

Genes affected

COX10 (HGNC:2260): (cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10) 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 heme A:farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion. [provided by RefSeq, Jul 2008]

COX10-DT (HGNC:38873): (COX10 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-14069543-C-T is Benign according to our data. Variant chr17-14069543-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321806.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0237 (3603/152312) while in subpopulation NFE AF= 0.0392 (2670/68028). AF 95% confidence interval is 0.038. There are 77 homozygotes in gnomad4. There are 1589 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 77 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX10	NM_001303.4	c.-63C>T		5_prime_UTR_variant	1/7	ENST00000261643.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX10	ENST00000261643.8	c.-63C>T		5_prime_UTR_variant	1/7	1	NM_001303.4	P1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3604 AN: 152192 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0392

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0339 AC: 49098 AN: 1447366 Hom.: 1006 Cov.: 30 AF XY: 0.0330 AC XY: 23764 AN XY: 720336

Gnomad4 AFR exome AF: 0.00494

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.00788

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0404

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0237 AC: 3603 AN: 152312 Hom.: 77 Cov.: 32 AF XY: 0.0213 AC XY: 1589 AN XY: 74474

Gnomad4 AFR AF: 0.00697

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0392

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0313 Hom.: 18

Bravo AF: 0.0238

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs77877576; hg19: chr17-13972860;