chr8-96231406-G-A

Position:

• chr8-96231406-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001254752.2(UQCRB):​c.368C>T​(p.Pro123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,537,292 control chromosomes in the GnomAD database, including 1,431 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (100 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1331 hom.)
• Consequence: UQCRB NM_001254752.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002295643).
• BP6: Variant 8-96231406-G-A is Benign according to our data. Variant chr8-96231406-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 676767.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 = 0.0286 (4348/152290) while in subpopulation NFE AF= 0.0457 (3109/68026). AF 95% confidence interval is 0.0444. There are 100 homozygotes in gnomad4. There are 1986 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 100 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UQCRB	NM_006294.5	c.259-274C>T		intron_variant		ENST00000287022.10	NP_006285.1
UQCRB	NM_001254752.2	c.368C>T	p.Pro123Leu	missense_variant	4/5		NP_001241681.1
UQCRB	NM_001199975.3	c.163-274C>T		intron_variant			NP_001186904.1
UQCRB	NR_045639.2	n.383C>T		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UQCRB	ENST00000287022.10	c.259-274C>T		intron_variant		1	NM_006294.5	ENSP00000287022.5

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4348 AN: 152172 Hom.: 100 Cov.: 33

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0275 AC: 3596 AN: 130938 Hom.: 76 AF XY: 0.0270 AC XY: 1927 AN XY: 71486

Gnomad AFR exome AF: 0.00896

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.000188

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0447

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0407 AC: 56427 AN: 1385002 Hom.: 1331 Cov.: 32 AF XY: 0.0401 AC XY: 27391 AN XY: 683498

Gnomad4 AFR exome AF: 0.00703

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0471

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0254

Gnomad4 NFE exome AF: 0.0467

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0286 AC: 4348 AN: 152290 Hom.: 100 Cov.: 33 AF XY: 0.0267 AC XY: 1986 AN XY: 74472

Gnomad4 AFR AF: 0.00748

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0478

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0212

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0340 Hom.: 23

Bravo AF: 0.0276

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0501 AC: 193

ExAC AF: 0.0124 AC: 419

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0066	.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.027
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.19
MPC		0.079
ClinPred		0.0053	T
GERP RS		-1.2
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs36123415; hg19: chr8-97243634;