5-132866976-C-T

Position:

• chr5-132866976-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_014402.5(UQCRQ):​c.95C>T​(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: UQCRQ NM_014402.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.22

Genes affected

UQCRQ (HGNC:29594): (ubiquinol-cytochrome c reductase complex III subunit VII) This gene encodes a ubiquinone-binding protein of low molecular mass. This protein is a small core-associated protein and a subunit of ubiquinol-cytochrome c reductase complex III, which is part of the mitochondrial respiratory chain. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22614643).
• BP6: Variant 5-132866976-C-T is Benign according to our data. Variant chr5-132866976-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215350.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UQCRQ	NM_014402.5	c.95C>T	p.Thr32Ile	missense_variant	2/3	ENST00000378670.8	NP_055217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UQCRQ	ENST00000378670.8	c.95C>T	p.Thr32Ile	missense_variant	2/3	1	NM_014402.5	ENSP00000367939	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 215350). This variant has not been reported in the literature in individuals affected with UQCRQ-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 32 of the UQCRQ protein (p.Thr32Ile). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2012

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
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Uncertain	0.58	D;D;D
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.62	.;.;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D;D;D
Sift4G	Benign	0.070	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.33
MutPred		0.48		Gain of methylation at K33 (P = 0.0909);Gain of methylation at K33 (P = 0.0909);Gain of methylation at K33 (P = 0.0909);
MVP		0.53
MPC		0.65
ClinPred		0.32	T
GERP RS		-1.3
Varity_R		0.34
gMVP		0.75

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

Other links and lift over

dbSNP: rs863224260; hg19: chr5-132202668;