11-74003826-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003356.4(UCP3):c.824+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,594,040 control chromosomes in the GnomAD database, including 313 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (166 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (147 hom.)
• Consequence: UCP3 NM_003356.4 splice_donor
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 7.71

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 -16 ACMG points.

• BP6: Variant 11-74003826-C-T is Benign according to our data. Variant chr11-74003826-C-T is described in ClinVar as [Benign]. Clinvar id is 7578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCP3	NM_003356.4	c.824+1G>A		splice_donor_variant		ENST00000314032.9
UCP3	XM_047427519.1	c.824+1G>A		splice_donor_variant
UCP3	NM_022803.3	c.825G>A	p.Gly275=	synonymous_variant	6/6
UCP3	XR_007062495.1	n.1028G>A		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP3	ENST00000314032.9	c.824+1G>A		splice_donor_variant		1	NM_003356.4	P1
UCP3	ENST00000426995.2	c.825G>A	p.Gly275=	synonymous_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3873 AN: 152184 Hom.: 166 Cov.: 33

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00657 AC: 1559 AN: 237186 Hom.: 54 AF XY: 0.00471 AC XY: 602 AN XY: 127790

Gnomad AFR exome AF: 0.0833

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000325

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00266 AC: 3837 AN: 1441738 Hom.: 147 Cov.: 31 AF XY: 0.00237 AC XY: 1697 AN XY: 715230

Gnomad4 AFR exome AF: 0.0903

Gnomad4 AMR exome AF: 0.00527

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000324

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.00661

GnomAD4 genome AF: 0.0255 AC: 3883 AN: 152302 Hom.: 166 Cov.: 33 AF XY: 0.0243 AC XY: 1810 AN XY: 74486

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00906 Hom.: 23

Bravo AF: 0.0294

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0820 AC: 361

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00772 AC: 937

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2019	This variant is associated with the following publications: (PMID: 9769326, 25525159, 22344438, 10618503) -

Morbid obesity Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

UCP3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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

UCP3 POLYMORPHISM, EXON 6 SPLICE DONOR JUNCTION Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0e-37	P;P;P
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45476292; hg19: chr11-73714871;