rs77877576

Variant names:

• chr17-14069543-C-T
• rs77877576
• NM_001303.4:c.-63C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.17
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -18 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 Benign/Likely_benign. ClinVar VariationId is 321806.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 = 0.0237 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 77 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303.4. 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
	COX10	NM_001303.4	MANE Select	c.-63C>T		5_prime_UTR	Exon 1 of 7	NP_001294.2
	COX10-DT	NR_049718.1		n.-85G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX10	ENST00000261643.8	TSL:1 MANE Select	c.-63C>T		5_prime_UTR	Exon 1 of 7	ENSP00000261643.3	Q12887-1
	COX10	ENST00000886734.1		c.-63C>T		5_prime_UTR	Exon 1 of 6	ENSP00000556793.1
	COX10	ENST00000886733.1		c.-63C>T		5_prime_UTR	Exon 1 of 5	ENSP00000556792.1

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

African (AFR) AF: 0.00494 AC: 164 AN: 33188

American (AMR) AF: 0.0172 AC: 760 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 366 AN: 25946

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39486

South Asian (SAS) AF: 0.00788 AC: 672 AN: 85310

European-Finnish (FIN) AF: 0.0114 AC: 602 AN: 52738

Middle Eastern (MID) AF: 0.0469 AC: 244 AN: 5204

European-Non Finnish (NFE) AF: 0.0404 AC: 44538 AN: 1101436

Other (OTH) AF: 0.0292 AC: 1747 AN: 59790

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

African (AFR) AF: 0.00697 AC: 290 AN: 41580

American (AMR) AF: 0.0224 AC: 343 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4824

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10620

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0392 AC: 2670 AN: 68028

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0337 Hom.: 128

Bravo AF: 0.0238

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.92
PhyloP100		2.2
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=282/18	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

Other links and lift over

dbSNP: rs77877576; hg19: chr17-13972860;