rs8179180

chr11-74007018-C-Gchr11-74007018-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003356.4(UCP3):c.25G>C(p.Val9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V9M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UCP3 NM_003356.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056482196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCP3	NM_003356.4	c.25G>C	p.Val9Leu	missense_variant	2/7	ENST00000314032.9
UCP3	NM_022803.3	c.25G>C	p.Val9Leu	missense_variant	2/6
UCP3	XM_047427519.1	c.25G>C	p.Val9Leu	missense_variant	1/6
UCP3	XR_007062495.1	n.228G>C		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP3	ENST00000314032.9	c.25G>C	p.Val9Leu	missense_variant	2/7	1	NM_003356.4	P1
UCP3	ENST00000426995.2	c.25G>C	p.Val9Leu	missense_variant	2/6	1
UCP3	ENST00000544614.1	c.25G>C	p.Val9Leu	missense_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	8.3
Dann	Benign	0.96
DEOGEN2	Benign	0.066	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.74	T;T;.
Polyphen		0.0070	B;.;.
Vest4		0.058
MutPred		0.24		Gain of glycosylation at P11 (P = 0.123);Gain of glycosylation at P11 (P = 0.123);Gain of glycosylation at P11 (P = 0.123);
MVP		0.35
MPC		0.042
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.049
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8179180; hg19: chr11-73718063;