11-74007018-C-T

Variant names:

• chr11-74007018-C-T
• rs8179180
• NM_003356.4:c.25G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003356.4(UCP3):​c.25G>A​(p.Val9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,050 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V9V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (59 hom.)
• Consequence: UCP3 NM_003356.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019788444).
• BP6: Variant 11-74007018-C-T is Benign according to our data. Variant chr11-74007018-C-T is described in ClinVar as Benign. ClinVar VariationId is 768467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2153/152290) while in subpopulation AFR AF = 0.047 (1953/41544). AF 95% confidence interval is 0.0453. There are 47 homozygotes in GnomAd4. There are 1026 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP3	NM_003356.4	MANE Select	c.25G>A	p.Val9Met	missense	Exon 2 of 7	NP_003347.1	P55916-1
	UCP3	NM_022803.3		c.25G>A	p.Val9Met	missense	Exon 2 of 6	NP_073714.1	P55916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP3	ENST00000314032.9	TSL:1 MANE Select	c.25G>A	p.Val9Met	missense	Exon 2 of 7	ENSP00000323740.4	P55916-1
	UCP3	ENST00000426995.2	TSL:1	c.25G>A	p.Val9Met	missense	Exon 2 of 6	ENSP00000392143.2	P55916-2
	UCP3	ENST00000963037.1		c.25G>A	p.Val9Met	missense	Exon 2 of 7	ENSP00000633096.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2146 AN: 152172 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00444 AC: 1114 AN: 251116 AF XY: 0.00345

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00222 AC: 3252 AN: 1461760 Hom.: 59 Cov.: 31 AF XY: 0.00201 AC XY: 1465 AN XY: 727182

African (AFR) AF: 0.0496 AC: 1660 AN: 33478

American (AMR) AF: 0.00326 AC: 146 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86254

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53312

Middle Eastern (MID) AF: 0.0191 AC: 110 AN: 5768

European-Non Finnish (NFE) AF: 0.000836 AC: 930 AN: 1111998

Other (OTH) AF: 0.00517 AC: 312 AN: 60394

GnomAD4 genome AF: 0.0141 AC: 2153 AN: 152290 Hom.: 47 Cov.: 32 AF XY: 0.0138 AC XY: 1026 AN XY: 74472

African (AFR) AF: 0.0470 AC: 1953 AN: 41544

American (AMR) AF: 0.00542 AC: 83 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00590 Hom.: 31

Bravo AF: 0.0157

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0500 AC: 220

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00548 AC: 665

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.054
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.15
Sift	Benign	0.080	T
Sift4G	Benign	0.22	T
Polyphen		0.50	P
Vest4		0.081
MVP		0.48
MPC		0.048
ClinPred		0.0065	T
GERP RS		3.5
PromoterAI		0.025	Neutral
Varity_R		0.036
gMVP		0.41
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8179180; hg19: chr11-73718063;