8-96231116-TC-T

Position:

• chr8-96231116-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006294.5(UQCRB):​c.274delG​(p.Glu92fs) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UQCRB NM_006294.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.61

Genes affected

UQCRB (HGNC:12582): (ubiquinol-cytochrome c reductase binding protein) This gene encodes a subunit of the ubiquinol-cytochrome c oxidoreductase complex, which consists of one mitochondrial-encoded and 10 nuclear-encoded subunits. The protein encoded by this gene binds ubiquinone and participates in the transfer of electrons when ubiquinone is bound. This protein plays an important role in hypoxia-induced angiogenesis through mitochondrial reactive oxygen species-mediated signaling. Mutations in this gene are associated with mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. Related pseudogenes have been identified on chromosomes 1, 5 and X. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.185 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-96231116-TC-T is Pathogenic according to our data. Variant chr8-96231116-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 215348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UQCRB	NM_006294.5	c.274delG	p.Glu92fs	frameshift_variant	4/4	ENST00000287022.10	NP_006285.1
UQCRB	NM_001254752.2	c.411delG	p.Asn138fs	frameshift_variant	5/5		NP_001241681.1
UQCRB	NM_001199975.3	c.178delG	p.Glu60fs	frameshift_variant	5/5		NP_001186904.1
UQCRB	NR_045639.2	n.579delG		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UQCRB	ENST00000287022.10	c.274delG	p.Glu92fs	frameshift_variant	4/4	1	NM_006294.5	ENSP00000287022.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2013

c.274delG: p.Glu92AsnfsX4 (E92Nfsx4) in exon 4 of the UQCRB gene (NM_006294.3). The normal sequence with the base that is deleted in braces is: CCTT{delG}AACC. The c.274delG mutation in the UQCRB gene causes a frameshift starting with codon Glutamic acid 92, changes this amino acid to an Asparagine residue and creates a Stop codon at position 3 of the new reading frame, denoted p.Glu93AsnfsX4. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is considered to be a disease-causing mutation. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 16

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224259; hg19: chr8-97243344;