chr4-140562322-G-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2
The NM_021833.5(UCP1):c.680C>T(p.Thr227Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,128 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.00072 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 15 hom. )
Consequence
UCP1
NM_021833.5 missense
NM_021833.5 missense
Scores
3
10
5
Clinical Significance
Conservation
PhyloP100: 7.96
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.028290689).
BP6
?
Variant 4-140562322-G-A is Benign according to our data. Variant chr4-140562322-G-A is described in ClinVar as [Benign]. Clinvar id is 773711.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High Homozygotes in GnomAd at 3 gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UCP1 | NM_021833.5 | c.680C>T | p.Thr227Ile | missense_variant | 5/6 | ENST00000262999.4 | |
UCP1 | XM_005263206.4 | c.677C>T | p.Thr226Ile | missense_variant | 5/6 | ||
UCP1 | XM_011532228.3 | c.680C>T | p.Thr227Ile | missense_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UCP1 | ENST00000262999.4 | c.680C>T | p.Thr227Ile | missense_variant | 5/6 | 1 | NM_021833.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000730 AC: 111AN: 152148Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00198 AC: 499AN: 251440Hom.: 4 AF XY: 0.00280 AC XY: 381AN XY: 135886
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GnomAD4 exome AF: 0.00131 AC: 1922AN: 1461862Hom.: 15 Cov.: 31 AF XY: 0.00175 AC XY: 1272AN XY: 727236
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GnomAD4 genome ? AF: 0.000716 AC: 109AN: 152266Hom.: 2 Cov.: 32 AF XY: 0.000873 AC XY: 65AN XY: 74472
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at