rs2229707

Positions:

• chr11-74006202-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003356.4(UCP3):​c.304G>A​(p.Val102Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00769 in 1,614,100 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (339 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (337 hom.)
• Consequence: UCP3 NM_003356.4 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: 5.62

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023040771).
• BP6: Variant 11-74006202-C-T is Benign according to our data. Variant chr11-74006202-C-T is described in ClinVar as [Benign]. Clinvar id is 7576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCP3	NM_003356.4	c.304G>A	p.Val102Ile	missense_variant	3/7	ENST00000314032.9
UCP3	NM_022803.3	c.304G>A	p.Val102Ile	missense_variant	3/6
UCP3	XM_047427519.1	c.304G>A	p.Val102Ile	missense_variant	2/6
UCP3	XR_007062495.1	n.507G>A		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP3	ENST00000314032.9	c.304G>A	p.Val102Ile	missense_variant	3/7	1	NM_003356.4	P1
UCP3	ENST00000426995.2	c.304G>A	p.Val102Ile	missense_variant	3/6	1
UCP3	ENST00000544614.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5638 AN: 152154 Hom.: 336 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0102 AC: 2547 AN: 250432 Hom.: 133 AF XY: 0.00756 AC XY: 1024 AN XY: 135490

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00784

GnomAD4 exome AF: 0.00462 AC: 6758 AN: 1461828 Hom.: 337 Cov.: 33 AF XY: 0.00400 AC XY: 2912 AN XY: 727210

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.00789

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000997

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0371 AC: 5655 AN: 152272 Hom.: 339 Cov.: 33 AF XY: 0.0353 AC XY: 2629 AN XY: 74468

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.00725 Hom.: 71

Bravo AF: 0.0411

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.119 AC: 524

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0126 AC: 1528

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity, severe, and type II diabetes Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

UCP3 POLYMORPHISM G/A Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	0.015
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.0015	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.044	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.045	B;.
Vest4		0.14
MPC		0.037
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.29
gMVP		0.49

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

Other links and lift over

dbSNP: rs2229707; hg19: chr11-73717247;