rs2270565

Variant names:

• chr4-140562317-T-A
• rs2270565
• NM_021833.5:c.685A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-140562317-T-A
• chr4-140562317-T-C

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 36 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
UCP1	NM_021833.5	c.685A>T	p.Met229Leu	missense_variant	Exon 5 of 6	ENST00000262999.4	NP_068605.1
UCP1	NM_001440546.1	c.682A>T	p.Met228Leu	missense_variant	Exon 5 of 6		NP_001427475.1
UCP1	XM_011532228.3	c.685A>T	p.Met229Leu	missense_variant	Exon 5 of 6		XP_011530530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP1	ENST00000262999.4	c.685A>T	p.Met229Leu	missense_variant	Exon 5 of 6	1	NM_021833.5	ENSP00000262999.3

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

GnomAD2 exomes AF: 0.0890 AC: 22371 AN: 251420 AF XY: 0.0901

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 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

African (AFR) AF: 0.0231 AC: 774 AN: 33480

American (AMR) AF: 0.117 AC: 5240 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 2599 AN: 26136

East Asian (EAS) AF: 0.0891 AC: 3538 AN: 39696

South Asian (SAS) AF: 0.114 AC: 9819 AN: 86256

European-Finnish (FIN) AF: 0.0912 AC: 4871 AN: 53412

Middle Eastern (MID) AF: 0.0756 AC: 436 AN: 5766

European-Non Finnish (NFE) AF: 0.0780 AC: 86709 AN: 1111988

Other (OTH) AF: 0.0762 AC: 4602 AN: 60396

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

African (AFR) AF: 0.0237 AC: 985 AN: 41508

American (AMR) AF: 0.0868 AC: 1326 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.0917 AC: 475 AN: 5180

South Asian (SAS) AF: 0.111 AC: 534 AN: 4812

European-Finnish (FIN) AF: 0.0880 AC: 932 AN: 10586

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0763 AC: 5188 AN: 67984

Other (OTH) AF: 0.0672 AC: 142 AN: 2112

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
PhyloP100		1.1
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
Mutation Taster		=98/2	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: rs2270565; hg19: chr4-141483471; COSMIC: COSV53767817;