rs6536991

Variant names:

• chr4-140560427-T-C
• rs6536991
• NM_021833.5:c.810-417A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021833.5(UCP1):​c.810-417A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 152,042 control chromosomes in the GnomAD database, including 9,921 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9921 hom., cov: 32)
• Consequence: UCP1 NM_021833.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 12 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 (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCP1	NM_021833.5	c.810-417A>G		intron_variant	Intron 5 of 5	ENST00000262999.4	NP_068605.1
UCP1	XM_011532228.3	c.*293A>G		3_prime_UTR_variant	Exon 6 of 6		XP_011530530.1
UCP1	NM_001440546.1	c.807-417A>G		intron_variant	Intron 5 of 5		NP_001427475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCP1	ENST00000262999.4	c.810-417A>G		intron_variant	Intron 5 of 5	1	NM_021833.5	ENSP00000262999.3

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50746 AN: 151924 Hom.: 9903 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.323

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.334 AC: 50802 AN: 152042 Hom.: 9921 Cov.: 32 AF XY: 0.336 AC XY: 24956 AN XY: 74314

African (AFR) AF: 0.542 AC: 22454 AN: 41440

American (AMR) AF: 0.334 AC: 5112 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 929 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1093 AN: 5164

South Asian (SAS) AF: 0.354 AC: 1704 AN: 4810

European-Finnish (FIN) AF: 0.253 AC: 2679 AN: 10576

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15839 AN: 67982

Other (OTH) AF: 0.320 AC: 675 AN: 2108

Alfa AF: 0.263 Hom.: 22731

Bravo AF: 0.348

Asia WGS AF: 0.343 AC: 1197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.69
DANN	Benign	0.48
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs6536991; hg19: chr4-141481581;