11-74006209-A-G

Position:

• chr11-74006209-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003356.4(UCP3):​c.297T>C​(p.Tyr99Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,780 control chromosomes in the GnomAD database, including 64,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11351 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53134 hom.)
• Consequence: UCP3 NM_003356.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.886

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-74006209-A-G is Benign according to our data. Variant chr11-74006209-A-G is described in ClinVar as [Benign]. Clinvar id is 1267154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.886 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCP3	NM_003356.4	c.297T>C	p.Tyr99Tyr	synonymous_variant	3/7	ENST00000314032.9	NP_003347.1
UCP3	NM_022803.3	c.297T>C	p.Tyr99Tyr	synonymous_variant	3/6		NP_073714.1
UCP3	XM_047427519.1	c.297T>C	p.Tyr99Tyr	synonymous_variant	2/6		XP_047283475.1
UCP3	XR_007062495.1	n.500T>C		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCP3	ENST00000314032.9	c.297T>C	p.Tyr99Tyr	synonymous_variant	3/7	1	NM_003356.4	ENSP00000323740.4
UCP3	ENST00000426995.2	c.297T>C	p.Tyr99Tyr	synonymous_variant	3/6	1		ENSP00000392143.2
UCP3	ENST00000544614.1	c.*8T>C		downstream_gene_variant		4		ENSP00000445279.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53459 AN: 151956 Hom.: 11322 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.274 AC: 68645 AN: 250314 Hom.: 10940 AF XY: 0.270 AC XY: 36594 AN XY: 135422

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.261 AC: 380863 AN: 1461704 Hom.: 53134 Cov.: 42 AF XY: 0.260 AC XY: 188906 AN XY: 727148

Gnomad4 AFR exome AF: 0.620

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.352 AC: 53533 AN: 152076 Hom.: 11351 Cov.: 32 AF XY: 0.353 AC XY: 26203 AN XY: 74322

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.274

Alfa AF: 0.261 Hom.: 3462

Bravo AF: 0.346

Asia WGS AF: 0.303 AC: 1053 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.222

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.27
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1800006; hg19: chr11-73717254; COSMIC: COSV58368219; COSMIC: COSV58368219;