chr5-149826745-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_133263.4(PPARGC1B):​c.325G>A​(p.Gly109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,906 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

PPARGC1B
NM_133263.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00907135).
BS2
High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPARGC1BNM_133263.4 linkuse as main transcriptc.325G>A p.Gly109Ser missense_variant 3/12 ENST00000309241.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPARGC1BENST00000309241.10 linkuse as main transcriptc.325G>A p.Gly109Ser missense_variant 3/121 NM_133263.4 P2Q86YN6-1
PPARGC1BENST00000394320.7 linkuse as main transcriptc.325G>A p.Gly109Ser missense_variant 3/111 A2Q86YN6-3
PPARGC1BENST00000360453.8 linkuse as main transcriptc.325G>A p.Gly109Ser missense_variant 3/111 A2Q86YN6-5
PPARGC1BENST00000403750.5 linkuse as main transcriptc.250G>A p.Gly84Ser missense_variant 3/112 A2Q86YN6-6

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152068
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00806
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000302
AC:
76
AN:
251410
Hom.:
1
AF XY:
0.000287
AC XY:
39
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00705
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000140
AC:
204
AN:
1461838
Hom.:
2
Cov.:
32
AF XY:
0.000142
AC XY:
103
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00597
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152068
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00806
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000510
Hom.:
0
Bravo
AF:
0.000253
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000214
AC:
26
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 21, 2021The c.325G>A (p.G109S) alteration is located in exon 3 (coding exon 3) of the PPARGC1B gene. This alteration results from a G to A substitution at nucleotide position 325, causing the glycine (G) at amino acid position 109 to be replaced by a serine (S). 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
0.093
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
.;.;D;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.091
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.72
T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.0091
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;L;.
MutationTaster
Benign
0.91
D;D;D;D
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-3.2
D;D;D;D
REVEL
Benign
0.054
Sift
Benign
0.066
T;T;T;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.10
B;P;B;.
Vest4
0.47
MVP
0.34
MPC
0.63
ClinPred
0.19
T
GERP RS
2.7
Varity_R
0.10
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs150279088; hg19: chr5-149206308; API