rs45539933

Positions:

• chr4-140567914-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021833.5(UCP1):​c.190G>A​(p.Ala64Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0784 in 1,614,094 control chromosomes in the GnomAD database, including 5,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.077 (469 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4805 hom.)
• Consequence: UCP1 NM_021833.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17

Genes affected

UCP1 (HGNC:12517): (uncoupling protein 1) Mitochondrial uncoupling proteins (UCP) are members of the 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. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene is expressed only in brown adipose tissue, a specialized tissue which functions to produce heat. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023334324).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCP1	NM_021833.5	c.190G>A	p.Ala64Thr	missense_variant	2/6	ENST00000262999.4	NP_068605.1
UCP1	XM_005263206.4	c.190G>A	p.Ala64Thr	missense_variant	2/6		XP_005263263.1
UCP1	XM_011532228.3	c.190G>A	p.Ala64Thr	missense_variant	2/6		XP_011530530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCP1	ENST00000262999.4	c.190G>A	p.Ala64Thr	missense_variant	2/6	1	NM_021833.5	ENSP00000262999	P1

Frequencies

GnomAD3 genomes AF: 0.0774 AC: 11769 AN: 152100 Hom.: 467 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.0840

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0832

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0731

GnomAD3 exomes AF: 0.0874 AC: 21969 AN: 251494 Hom.: 1138 AF XY: 0.0874 AC XY: 11879 AN XY: 135920

Gnomad AFR exome AF: 0.0787

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.0688

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0760

Gnomad OTH exome AF: 0.0814

GnomAD4 exome AF: 0.0785 AC: 114800 AN: 1461876 Hom.: 4805 Cov.: 32 AF XY: 0.0792 AC XY: 57580 AN XY: 727238

Gnomad4 AFR exome AF: 0.0803

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.0783

Gnomad4 EAS exome AF: 0.0726

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0872

Gnomad4 NFE exome AF: 0.0745

Gnomad4 OTH exome AF: 0.0749

GnomAD4 genome AF: 0.0774 AC: 11789 AN: 152218 Hom.: 469 Cov.: 32 AF XY: 0.0787 AC XY: 5862 AN XY: 74446

Gnomad4 AFR AF: 0.0794

Gnomad4 AMR AF: 0.0836

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.0690

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0832

Gnomad4 NFE AF: 0.0724

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0760 Hom.: 752

Bravo AF: 0.0778

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0768 AC: 296

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.0745 AC: 641

ExAC AF: 0.0871 AC: 10574

Asia WGS AF: 0.0860 AC: 298 AN: 3478

EpiCase AF: 0.0740

EpiControl AF: 0.0724

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	4.1	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.095
MPC		0.16
ClinPred		0.0065	T
GERP RS		5.5
Varity_R		0.082
gMVP		0.50

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: rs45539933; hg19: chr4-141489068; COSMIC: COSV53767548;