17-54968611-AA-C

Position:

• chr17-54968611-AA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004375.5(COX11):​c.35_36delinsG​(p.Val12GlyfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: COX11 NM_004375.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.127

Genes affected

COX11 (HGNC:2261): (cytochrome c oxidase copper chaperone COX11) 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 a heme A biosynthetic enzyme involved in COX formation, according to the yeast mutant studies. However, the studies in Rhodobacter sphaeroides suggest that this gene is not required for heme A biosynthesis, but required for stable formation of the Cu(B) and magnesium centers of COX. This human protein is predicted to contain a transmembrane domain localized in the mitochondrial inner membrane. Multiple transcript variants encoding different isoforms have been found for this gene. A related pseudogene has been found on chromosome 6. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-54968611-AA-C is Pathogenic according to our data. Variant chr17-54968611-AA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2443971.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX11	NM_004375.5	c.35_36delinsG	p.Val12GlyfsTer21	frameshift_variant	1/4	ENST00000299335.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COX11	ENST00000299335.8	c.35_36delinsG	p.Val12GlyfsTer21	frameshift_variant	1/4	1	NM_004375.5	P1
COX11	ENST00000576370.5	c.35_36delinsG	p.Val12GlyfsTer21	frameshift_variant, NMD_transcript_variant	1/5	1
COX11	ENST00000571584.1	c.35_36delinsG	p.Val12GlyfsTer21	frameshift_variant	1/3	2
COX11	ENST00000572558.5	c.35_36delinsG	p.Val12GlyfsTer21	frameshift_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 23 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-53045972;