11-74005424-A-G

Variant names:

• chr11-74005424-A-G
• rs3781907
• NM_003356.4:c.541+306T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003356.4(UCP3):​c.541+306T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 151,928 control chromosomes in the GnomAD database, including 6,750 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (6750 hom., cov: 32)
• Consequence: UCP3 NM_003356.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.581
• Publications: 27 publications found

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]

ENSG00000298570 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP3	NM_003356.4	c.541+306T>C		intron_variant	Intron 4 of 6	ENST00000314032.9	NP_003347.1
UCP3	NM_022803.3	c.541+306T>C		intron_variant	Intron 4 of 5		NP_073714.1
UCP3	XM_047427519.1	c.541+306T>C		intron_variant	Intron 3 of 5		XP_047283475.1
UCP3	XR_007062495.1	n.744+306T>C		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP3	ENST00000314032.9	c.541+306T>C		intron_variant	Intron 4 of 6	1	NM_003356.4	ENSP00000323740.4
UCP3	ENST00000426995.2	c.541+306T>C		intron_variant	Intron 4 of 5	1		ENSP00000392143.2
ENSG00000298570	ENST00000756620.1	n.419+407A>G		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44822 AN: 151810 Hom.: 6756 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.0949

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.295 AC: 44836 AN: 151928 Hom.: 6750 Cov.: 32 AF XY: 0.297 AC XY: 22030 AN XY: 74246

African (AFR) AF: 0.313 AC: 12982 AN: 41424

American (AMR) AF: 0.249 AC: 3796 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1138 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2092 AN: 5156

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4808

European-Finnish (FIN) AF: 0.335 AC: 3541 AN: 10562

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19379 AN: 67920

Other (OTH) AF: 0.251 AC: 531 AN: 2114

Alfa AF: 0.277 Hom.: 11101

Bravo AF: 0.286

Asia WGS AF: 0.330 AC: 1145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.78
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3781907; hg19: chr11-73716469;