4-140563206-T-G

Position:

• chr4-140563206-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021833.5(UCP1):​c.532A>C​(p.Thr178Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UCP1 NM_021833.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0400

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4135599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCP1	NM_021833.5	c.532A>C	p.Thr178Pro	missense_variant	4/6	ENST00000262999.4	NP_068605.1
UCP1	XM_005263206.4	c.529A>C	p.Thr177Pro	missense_variant	4/6		XP_005263263.1
UCP1	XM_011532228.3	c.532A>C	p.Thr178Pro	missense_variant	4/6		XP_011530530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCP1	ENST00000262999.4	c.532A>C	p.Thr178Pro	missense_variant	4/6	1	NM_021833.5	ENSP00000262999.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.532A>C (p.T178P) alteration is located in exon 4 (coding exon 4) of the UCP1 gene. This alteration results from a A to C substitution at nucleotide position 532, causing the threonine (T) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.00045	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.44
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.42
MutPred		0.45		Loss of glycosylation at K175 (P = 0.115);
MVP		0.73
MPC		0.69
ClinPred		0.33	T
GERP RS		0.93
Varity_R		0.52
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-141484360;