chr17-14074261-G-A

Variant names:

• chr17-14074261-G-A
• rs78734063
• NM_001303.4:c.44-62G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001303.4(COX10):​c.44-62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,603,042 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.016 (229 hom.)
• Consequence: COX10 NM_001303.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.407

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-14074261-G-A is Benign according to our data. Variant chr17-14074261-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1765/152286) while in subpopulation NFE AF = 0.0174 (1184/68010). AF 95% confidence interval is 0.0166. There are 16 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX10	NM_001303.4	c.44-62G>A		intron_variant	Intron 1 of 6	ENST00000261643.8	NP_001294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX10	ENST00000261643.8	c.44-62G>A		intron_variant	Intron 1 of 6	1	NM_001303.4	ENSP00000261643.3

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1766 AN: 152168 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.0156 AC: 22564 AN: 1450756 Hom.: 229 AF XY: 0.0155 AC XY: 11214 AN XY: 722462

Gnomad4 AFR exome AF: 0.00241 AC: 80 AN: 33224

Gnomad4 AMR exome AF: 0.00821 AC: 367 AN: 44694

Gnomad4 ASJ exome AF: 0.0249 AC: 648 AN: 26040

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39606

Gnomad4 SAS exome AF: 0.0127 AC: 1095 AN: 86048

Gnomad4 FIN exome AF: 0.00962 AC: 506 AN: 52576

Gnomad4 NFE exome AF: 0.0171 AC: 18810 AN: 1102822

Gnomad4 Remaining exome AF: 0.0159 AC: 953 AN: 59992

GnomAD4 genome AF: 0.0116 AC: 1765 AN: 152286 Hom.: 16 Cov.: 32 AF XY: 0.0109 AC XY: 814 AN XY: 74456

Gnomad4 AFR AF: 0.00327 AC: 0.0032719 AN: 0.0032719

Gnomad4 AMR AF: 0.00726 AC: 0.0072568 AN: 0.0072568

Gnomad4 ASJ AF: 0.0291 AC: 0.0290899 AN: 0.0290899

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00994 AC: 0.009942 AN: 0.009942

Gnomad4 FIN AF: 0.0103 AC: 0.0102772 AN: 0.0102772

Gnomad4 NFE AF: 0.0174 AC: 0.0174092 AN: 0.0174092

Gnomad4 OTH AF: 0.0161 AC: 0.0160681 AN: 0.0160681

Alfa AF: 0.0137 Hom.: 25

Bravo AF: 0.0107

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.53
Mutation Taster		=100/0	polymorphism

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: rs78734063; hg19: chr17-13977578;