11-62671975-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000377953.4(UQCC3):​c.143G>A​(p.Arg48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

UQCC3
ENST00000377953.4 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.915
Variant links:
Genes affected
UQCC3 (HGNC:34399): (ubiquinol-cytochrome c reductase complex assembly factor 3) Complex III is a mitochondrial inner membrane protein complex that transfers electrons from ubiquinol to cytochrome c. This gene encodes a protein that functions in complex III assembly. Mutations in this gene result in Mitochondrial complex III deficiency, nuclear type 9. [provided by RefSeq, Dec 2014]
LBHD1 (HGNC:28351): (LBH domain containing 1) This gene shares three exons in common with another gene, chromosome 11 open reading frame 98 (GeneID:102288414), but the encoded protein uses a reading frame that is different from that of the chromosome 11 open reading frame 98 gene. [provided by RefSeq, Nov 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007163167).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UQCC3NM_001085372.3 linkuse as main transcriptc.143G>A p.Arg48Lys missense_variant 2/2 ENST00000377953.4 NP_001078841.1
LBHD1NM_024099.5 linkuse as main transcriptc.-422C>T 5_prime_UTR_variant 1/7 ENST00000354588.8 NP_077004.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UQCC3ENST00000377953.4 linkuse as main transcriptc.143G>A p.Arg48Lys missense_variant 2/21 NM_001085372.3 ENSP00000367189 P1
LBHD1ENST00000354588.8 linkuse as main transcriptc.-422C>T 5_prime_UTR_variant 1/71 NM_024099.5 ENSP00000346600 P1Q9BQE6-2
UQCC3ENST00000531323.1 linkuse as main transcriptc.143G>A p.Arg48Lys missense_variant 3/33 ENSP00000432692 P1
LBHD1ENST00000528862.2 linkuse as main transcriptc.93+152C>T intron_variant 3 ENSP00000434489

Frequencies

GnomAD3 genomes
AF:
0.000315
AC:
48
AN:
152256
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00262
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:
0.0000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000404
AC:
10
AN:
247396
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000871
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.000664
GnomAD4 exome
AF:
0.0000883
AC:
129
AN:
1461646
Hom.:
0
Cov.:
31
AF XY:
0.0000756
AC XY:
55
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
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:
0.0000998
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000315
AC:
48
AN:
152374
Hom.:
0
Cov.:
32
AF XY:
0.000362
AC XY:
27
AN XY:
74522
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000659
Hom.:
0
Bravo
AF:
0.000570
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 02, 2022In 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. This variant has not been reported in the literature in individuals affected with UQCC3-related conditions. This variant is present in population databases (rs199794771, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 48 of the UQCC3 protein (p.Arg48Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
0.088
DANN
Benign
0.70
DEOGEN2
Benign
0.30
T;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.44
.;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.0072
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N
PROVEAN
Benign
-0.76
N;N
REVEL
Benign
0.032
Sift
Benign
0.97
T;T
Sift4G
Benign
0.42
T;T
Polyphen
0.10
B;B
Vest4
0.094
MutPred
0.16
Gain of ubiquitination at R48 (P = 9e-04);Gain of ubiquitination at R48 (P = 9e-04);
MVP
0.061
MPC
0.38
ClinPred
0.032
T
GERP RS
-6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.068
gMVP
0.071

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs199794771; hg19: chr11-62439447; COSMIC: COSV53656666; COSMIC: COSV53656666; API