chr8-96231067-C-A

Position:

chr8-96231067-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_006294.5(UQCRB):c.324G>T(p.Trp108Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

UQCRB
NM_006294.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 6.49

Variant links:

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]

UQCRB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 8-96231067-C-A is Pathogenic according to our data. Variant chr8-96231067-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215347.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UQCRB	NM_006294.5 linkuse as main transcript	c.324G>T	p.Trp108Cys	missense_variant	4/4	ENST00000287022.10
UQCRB	NM_001199975.3 linkuse as main transcript	c.228G>T	p.Trp76Cys	missense_variant	5/5
UQCRB	NM_001254752.2 linkuse as main transcript	c.*38G>T		3_prime_UTR_variant	5/5
UQCRB	NR_045639.2 linkuse as main transcript	n.629G>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UQCRB	ENST00000287022.10 linkuse as main transcript	c.324G>T	p.Trp108Cys	missense_variant	4/4	1	NM_006294.5	P1	P14927-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461118

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2014	p.Trp108Cys (TGG>TGT): c.324 G>T in exon 4 of the UQCRB gene (NM_006294.3). The W108C likely pathogenic variant identified in the UQCRB gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The W108C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 108 of the UQCRB protein (p.Trp108Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UQCRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 215347). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Pathogenic

-10

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.63

MutPred

0.46

Loss of MoRF binding (P = 7e-04);

MVP

0.78

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over