11-74001663-GTCTC-GTCTCTCTC

Variant names:

• chr11-74001663-G-GTCTC
• rs3837411
• NM_003356.4:c.825-141_825-138dupGAGA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003356.4(UCP3):​c.825-141_825-138dupGAGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000702 in 712,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: UCP3 NM_003356.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.517
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.825-141_825-138dupGAGA		intron	N/A	NP_003347.1	P55916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCP3	ENST00000314032.9	TSL:1 MANE Select	c.825-138_825-137insGAGA		intron	N/A	ENSP00000323740.4	P55916-1
	UCP3	ENST00000963037.1		c.783-138_783-137insGAGA		intron	N/A	ENSP00000633096.1
	UCP3	ENST00000545271.1	TSL:4	n.515+76_515+77insGAGA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000674 AC: 1 AN: 148302 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.00000709 AC: 4 AN: 564410 Hom.: 0 Cov.: 7 AF XY: 0.0000134 AC XY: 4 AN XY: 299204

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15018

American (AMR) AF: 0.0000388 AC: 1 AN: 25742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18098

East Asian (EAS) AF: 0.00 AC: 0 AN: 31146

South Asian (SAS) AF: 0.00 AC: 0 AN: 55918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2868

European-Non Finnish (NFE) AF: 0.00000581 AC: 2 AN: 344504

Other (OTH) AF: 0.0000333 AC: 1 AN: 30020

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000101728), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148302 Hom.: 0 Cov.: 28 AF XY: 0.0000138 AC XY: 1 AN XY: 72254

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38708

American (AMR) AF: 0.00 AC: 0 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67706

Other (OTH) AF: 0.000490 AC: 1 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3837411; hg19: chr11-73712708;