11-74006209-A-G

Variant names:

• chr11-74006209-A-G
• rs1800006
• NM_003356.4:c.297T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003356.4(UCP3):​c.297T>C​(p.Tyr99Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,780 control chromosomes in the GnomAD database, including 64,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11351 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53134 hom.)
• Consequence: UCP3 NM_003356.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.886
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-74006209-A-G is Benign according to our data. Variant chr11-74006209-A-G is described in ClinVar as Benign. ClinVar VariationId is 1267154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.886 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

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.297T>C	p.Tyr99Tyr	synonymous	Exon 3 of 7	NP_003347.1	P55916-1
	UCP3	NM_022803.3		c.297T>C	p.Tyr99Tyr	synonymous	Exon 3 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.297T>C	p.Tyr99Tyr	synonymous	Exon 3 of 7	ENSP00000323740.4	P55916-1
	UCP3	ENST00000426995.2	TSL:1	c.297T>C	p.Tyr99Tyr	synonymous	Exon 3 of 6	ENSP00000392143.2	P55916-2
	UCP3	ENST00000963037.1		c.297T>C	p.Tyr99Tyr	synonymous	Exon 3 of 7	ENSP00000633096.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53459 AN: 151956 Hom.: 11322 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.274 AC: 68645 AN: 250314 AF XY: 0.270

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.261 AC: 380863 AN: 1461704 Hom.: 53134 Cov.: 42 AF XY: 0.260 AC XY: 188906 AN XY: 727148

African (AFR) AF: 0.620 AC: 20741 AN: 33480

American (AMR) AF: 0.160 AC: 7141 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6799 AN: 26132

East Asian (EAS) AF: 0.298 AC: 11831 AN: 39698

South Asian (SAS) AF: 0.257 AC: 22150 AN: 86254

European-Finnish (FIN) AF: 0.366 AC: 19500 AN: 53328

Middle Eastern (MID) AF: 0.189 AC: 1091 AN: 5768

European-Non Finnish (NFE) AF: 0.247 AC: 275149 AN: 1111956

Other (OTH) AF: 0.273 AC: 16461 AN: 60392

GnomAD4 genome AF: 0.352 AC: 53533 AN: 152076 Hom.: 11351 Cov.: 32 AF XY: 0.353 AC XY: 26203 AN XY: 74322

African (AFR) AF: 0.600 AC: 24865 AN: 41466

American (AMR) AF: 0.203 AC: 3109 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 896 AN: 3464

East Asian (EAS) AF: 0.308 AC: 1592 AN: 5164

South Asian (SAS) AF: 0.255 AC: 1228 AN: 4820

European-Finnish (FIN) AF: 0.381 AC: 4025 AN: 10574

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 17055 AN: 67994

Other (OTH) AF: 0.274 AC: 579 AN: 2112

Alfa AF: 0.266 Hom.: 3766

Bravo AF: 0.346

Asia WGS AF: 0.303 AC: 1053 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.27
DANN	Benign	0.34
PhyloP100		-0.89
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1800006; hg19: chr11-73717254; COSMIC: COSV58368219; COSMIC: COSV58368219;