rs869025575

Variant names:

• chr11-63976224-G-C
• rs869025575
• NM_004074.3:c.115-1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004074.3(COX8A):​c.115-1G>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COX8A NM_004074.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.83
• Publications: 2 publications found

Genes affected

COX8A (HGNC:2294): (cytochrome c oxidase subunit 8A) The protein encoded by this gene is the terminal enzyme of the respiratory chain, coupling the transfer of electrons from cytochrome c to molecular oxygen, with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane. In addition to 3 mitochondrially encoded subunits, which perform the catalytic function, the eukaryotic enzyme contains nuclear-encoded smaller subunits, ranging in number from 4 in some organisms to 10 in mammals. It has been proposed that nuclear-encoded subunits may be involved in the modulation of the catalytic function. This gene encodes one of the nuclear-encoded subunits. [provided by RefSeq, Jul 2008]

COX8A Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• mitochondrial complex IV deficiency, nuclear type 15

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000256100 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-63976224-G-C is Pathogenic according to our data. Variant chr11-63976224-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 222973.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004074.3. 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
	COX8A	NM_004074.3	MANE Select	c.115-1G>C		splice_acceptor intron	N/A	NP_004065.1	P10176

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX8A	ENST00000314133.4	TSL:1 MANE Select	c.115-1G>C		splice_acceptor intron	N/A	ENSP00000321260.3	P10176
	ENSG00000256100	ENST00000535431.1	TSL:5	n.175+1430G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		4.8
GERP RS		5.2
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.5
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: 50
DS_AL_spliceai		0.95		Position offset: 1

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

Other links and lift over

dbSNP: rs869025575; hg19: chr11-63743696;