11-74001507-G-C

Variant names:

• chr11-74001507-G-C
• rs8179179
• NM_003356.4:c.844C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003356.4(UCP3):​c.844C>G​(p.Arg282Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R282H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UCP3 NM_003356.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.72
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP3	NM_003356.4	c.844C>G	p.Arg282Gly	missense_variant	Exon 7 of 7	ENST00000314032.9	NP_003347.1
UCP3	XM_047427519.1	c.844C>G	p.Arg282Gly	missense_variant	Exon 6 of 6		XP_047283475.1
UCP3	XR_007062495.1	n.3134C>G		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP3	ENST00000314032.9	c.844C>G	p.Arg282Gly	missense_variant	Exon 7 of 7	1	NM_003356.4	ENSP00000323740.4
UCP3	ENST00000545271.1	n.535C>G		non_coding_transcript_exon_variant	Exon 2 of 2	4
ENSG00000298570	ENST00000756620.1	n.46+1092G>C		intron_variant	Intron 1 of 4
ENSG00000298594	ENST00000756716.1	n.*195G>C		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.90
Mutation Taster		=31/69	disease causing

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: rs8179179; hg19: chr11-73712552;