dbSNP rs17572019: PPARGC1B:p.Val279Ile (chr5-149832908-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_133263.4(PPARGC1B):c.835G>A(p.Val279Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 1,613,074 control chromosomes in the GnomAD database, including 5,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.070 ( 476 hom., cov: 32)

Exomes 𝑓: 0.082 ( 5212 hom. )

Consequence

PPARGC1B
NM_133263.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.967

Variant links:

Genes affected

PPARGC1B (HGNC:30022): (PPARG coactivator 1 beta) The protein encoded by this gene stimulates the activity of several transcription factors and nuclear receptors, including estrogen receptor alpha, nuclear respiratory factor 1, and glucocorticoid receptor. The encoded protein may be involved in fat oxidation, non-oxidative glucose metabolism, and the regulation of energy expenditure. This protein is downregulated in prediabetic and type 2 diabetes mellitus patients. Certain allelic variations in this gene increase the risk of the development of obesity. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

PPARGC1B 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=0.0014909208).

BP6

Variant 5-149832908-G-A is Benign according to our data. Variant chr5-149832908-G-A is described in ClinVar as [Benign]. Clinvar id is 1288207.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1B	NM_133263.4 link	c.835G>A	p.Val279Ile	missense_variant	Exon 5 of 12	ENST00000309241.10	NP_573570.3	Q86YN6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1B	ENST00000309241.10 link	c.835G>A	p.Val279Ile	missense_variant	Exon 5 of 12	1	NM_133263.4	ENSP00000312649.5		Q86YN6-1

Frequencies

GnomAD3 genomes

AF:

0.0703

AC:

10695

AN:

152114

Hom.:

476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0286

Gnomad AMI

AF:

0.0824

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.0615

Gnomad FIN

AF:

0.0460

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.0886

GnomAD3 exomes

AF:

0.0854

AC:

21193

AN:

248096

Hom.:

1108

AF XY:

0.0841

AC XY:

11328

AN XY:

134736

show subpopulations

Gnomad AFR exome

AF:

0.0280

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.0645

Gnomad SAS exome

AF:

0.0675

Gnomad FIN exome

AF:

0.0490

Gnomad NFE exome

AF:

0.0834

Gnomad OTH exome

AF:

0.0845

GnomAD4 exome

AF:

0.0816

AC:

119206

AN:

1460842

Hom.:

5212

Cov.:

AF XY:

0.0812

AC XY:

59010

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.0260

Gnomad4 AMR exome

AF:

0.148

Gnomad4 ASJ exome

AF:

0.148

Gnomad4 EAS exome

AF:

0.0577

Gnomad4 SAS exome

AF:

0.0655

Gnomad4 FIN exome

AF:

0.0500

Gnomad4 NFE exome

AF:

0.0824

Gnomad4 OTH exome

AF:

0.0841

GnomAD4 genome

AF:

0.0702

AC:

10694

AN:

152232

Hom.:

476

Cov.:

AF XY:

0.0712

AC XY:

5303

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0285

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.0596

Gnomad4 SAS

AF:

0.0612

Gnomad4 FIN

AF:

0.0460

Gnomad4 NFE

AF:

0.0798

Gnomad4 OTH

AF:

0.0882

Alfa

AF:

0.0829

Hom.:

1058

Bravo

AF:

0.0763

TwinsUK

AF:

0.0771

AC:

286

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0284

AC:

125

ESP6500EA

AF:

0.0834

AC:

717

ExAC

AF:

0.0802

AC:

9732

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

EpiCase

AF:

0.0876

EpiControl

AF:

0.0862

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.93

DANN

Benign

0.91

DEOGEN2

Benign

0.19

.;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.67

T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.0

.;M;M;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.30

N;N;N;N

REVEL

Benign

0.043

Sift

Benign

0.047

D;D;D;D

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.010

B;B;B;.

Vest4

0.034

MPC

0.14

ClinPred

0.010

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.064

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