11-74007018-C-T

Position:

chr11-74007018-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_003356.4(UCP3):c.25G>A(p.Val9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,050 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. V9V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 47 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 59 hom. )

Consequence

UCP3
NM_003356.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0540

Variant links:

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]

UCP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019788444).

BP6

Variant 11-74007018-C-T is Benign according to our data. Variant chr11-74007018-C-T is described in ClinVar as [Benign]. Clinvar id is 768467.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2153/152290) while in subpopulation AFR AF= 0.047 (1953/41544). AF 95% confidence interval is 0.0453. There are 47 homozygotes in gnomad4. There are 1026 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UCP3	NM_003356.4 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/7	ENST00000314032.9
UCP3	NM_022803.3 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/6
UCP3	XM_047427519.1 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	1/6
UCP3	XR_007062495.1 linkuse as main transcript	n.228G>A		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCP3	ENST00000314032.9 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/7	1	NM_003356.4	P1	P55916-1
UCP3	ENST00000426995.2 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	2/6	1			P55916-2
UCP3	ENST00000544614.1 linkuse as main transcript	c.25G>A	p.Val9Met	missense_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2146

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0470

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00444

AC:

1114

AN:

251116

Hom.:

AF XY:

0.00345

AC XY:

468

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.0511

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00222

AC:

3252

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1465

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0496

Gnomad4 AMR exome

AF:

0.00326

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000846

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000836

Gnomad4 OTH exome

AF:

0.00517

GnomAD4 genome

AF:

0.0141

AC:

2153

AN:

152290

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1026

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0470

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00363

Hom.:

Bravo

AF:

0.0157

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0500

AC:

220

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00548

AC:

665

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00148

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

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.3

L;L;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.42

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.22

T;T;.

Polyphen

0.50

P;.;.

Vest4

0.081

MVP

0.48

MPC

0.048

ClinPred

0.0065

GERP RS

3.5

Varity_R

0.036

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over