rs2270565

Positions:

• chr4-140562317-T-A

Variant summary

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

The NM_021833.5(UCP1):​c.685A>T​(p.Met229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,613,978 control chromosomes in the GnomAD database, including 5,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.066 (393 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5190 hom.)
• Consequence: UCP1 NM_021833.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12

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=0.0015224814).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCP1	NM_021833.5	c.685A>T	p.Met229Leu	missense_variant	5/6	ENST00000262999.4
UCP1	XM_005263206.4	c.682A>T	p.Met228Leu	missense_variant	5/6
UCP1	XM_011532228.3	c.685A>T	p.Met229Leu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP1	ENST00000262999.4	c.685A>T	p.Met229Leu	missense_variant	5/6	1	NM_021833.5	P1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10017 AN: 152016 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0872

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0890 AC: 22371 AN: 251420 Hom.: 1193 AF XY: 0.0901 AC XY: 12246 AN XY: 135874

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.0915

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0797

Gnomad OTH exome AF: 0.0851

GnomAD4 exome AF: 0.0811 AC: 118588 AN: 1461844 Hom.: 5190 Cov.: 32 AF XY: 0.0822 AC XY: 59748 AN XY: 727226

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0994

Gnomad4 EAS exome AF: 0.0891

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0912

Gnomad4 NFE exome AF: 0.0780

Gnomad4 OTH exome AF: 0.0762

GnomAD4 genome AF: 0.0658 AC: 10010 AN: 152134 Hom.: 393 Cov.: 32 AF XY: 0.0681 AC XY: 5065 AN XY: 74376

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.0868

Gnomad4 ASJ AF: 0.0974

Gnomad4 EAS AF: 0.0917

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0880

Gnomad4 NFE AF: 0.0763

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0786 Hom.: 174

Bravo AF: 0.0639

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0799 AC: 308

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.0793 AC: 682

ExAC AF: 0.0873 AC: 10595

Asia WGS AF: 0.0850 AC: 297 AN: 3478

EpiCase AF: 0.0791

EpiControl AF: 0.0783

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.60
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.68	N
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.16
Sift	Benign	0.26	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.20		Loss of glycosylation at S231 (P = 0.0947);
MPC		0.15
ClinPred		0.0026	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.62

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: rs2270565; hg19: chr4-141483471; COSMIC: COSV53767817;