rs104894319

Positions:

chr11-74005844-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_003356.4(UCP3):c.427C>T(p.Arg143*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,614,128 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). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

UCP3
NM_003356.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 2.58

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:

UCP3 (HGNC:):

UCP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 11-74005844-G-A is Benign according to our data. Variant chr11-74005844-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7577.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCP3	NM_003356.4 linkuse as main transcript	c.427C>T	p.Arg143*	stop_gained	4/7	ENST00000314032.9	NP_003347.1	P55916-1A0A0S2Z4G5
UCP3	NM_022803.3 linkuse as main transcript	c.427C>T	p.Arg143*	stop_gained	4/6		NP_073714.1	P55916-2
UCP3	XM_047427519.1 linkuse as main transcript	c.427C>T	p.Arg143*	stop_gained	3/6		XP_047283475.1
UCP3	XR_007062495.1 linkuse as main transcript	n.630C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCP3	ENST00000314032.9 linkuse as main transcript	c.427C>T	p.Arg143*	stop_gained	4/7	1	NM_003356.4	ENSP00000323740.4		P55916-1
UCP3	ENST00000426995.2 linkuse as main transcript	c.427C>T	p.Arg143*	stop_gained	4/6	1		ENSP00000392143.2		P55916-2

Frequencies

GnomAD3 genomes

AF:

0.00180

AC:

274

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.000644

AC:

162

AN:

251452

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00732

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000245

AC:

358

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00723

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00182

AC:

277

AN:

152238

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00583

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000476

Hom.:

Bravo

AF:

0.00210

ESP6500AA

AF:

0.00659

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 02, 2022	PS3_Moderate, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -

Obesity, severe, and type II diabetes

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Inherited obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

UCP3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

Vest4

0.98

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -9

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