rs192655642

Positions:

chr11-74006232-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003356.4(UCP3):c.274G>A(p.Ala92Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

UCP3
NM_003356.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.85

Variant links:

Genes affected

UCP3 (HGNC:12519): (uncoupling protein 3) Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. The different UCPs have tissue-specific expression; this gene is primarily expressed in skeletal muscle. This gene's protein product is postulated to protect mitochondria against lipid-induced oxidative stress. Expression levels of this gene increase when fatty acid supplies to mitochondria exceed their oxidation capacity and the protein enables the export of fatty acids from mitochondria. UCPs contain the three solcar protein domains typically found in MACPs. Two splice variants have been found for this gene.[provided by RefSeq, Nov 2008]

UCP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18226075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
UCP3	NM_003356.4 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	3/7	ENST00000314032.9	NP_003347.1
UCP3	NM_022803.3 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	3/6		NP_073714.1
UCP3	XM_047427519.1 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	2/6		XP_047283475.1
UCP3	XR_007062495.1 linkuse as main transcript	n.477G>A		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCP3	ENST00000314032.9 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	3/7	1	NM_003356.4	ENSP00000323740	P1	P55916-1
UCP3	ENST00000426995.2 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	3/6	1		ENSP00000392143		P55916-2
UCP3	ENST00000544614.1 linkuse as main transcript	c.274G>A	p.Ala92Thr	missense_variant	2/2	4		ENSP00000445279

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

250544

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000870

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 28, 2017

- -

UCP3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The UCP3 c.274G>A variant is predicted to result in the amino acid substitution p.Ala92Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.098% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.016

D;D;D

Sift4G

Benign

0.12

T;T;.

Polyphen

0.53

P;.;.

Vest4

0.77

MVP

0.72

MPC

0.15

ClinPred

0.42

GERP RS

4.6

Varity_R

0.45

gMVP

0.55

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