rs11959820

Positions:

• chr5-149832947-C-A
• chr5-149832947-C-G
• chr5-149832947-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000309241.10(PPARGC1B):​c.874C>A​(p.Arg292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0426 in 1,613,134 control chromosomes in the GnomAD database, including 2,546 homozygotes. In-silico tool predicts 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.

• Frequency:
  • Genomes: 𝑓 0.076 (748 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1798 hom.)
• Consequence: PPARGC1B ENST00000309241.10 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.86

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016933084).
• BP6: Variant 5-149832947-C-A is Benign according to our data. Variant chr5-149832947-C-A is described in ClinVar as [Benign]. Clinvar id is 1288654.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARGC1B	NM_133263.4	c.874C>A	p.Arg292Ser	missense_variant	5/12	ENST00000309241.10	NP_573570.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPARGC1B	ENST00000309241.10	c.874C>A	p.Arg292Ser	missense_variant	5/12	1	NM_133263.4	ENSP00000312649	P2
PPARGC1B	ENST00000394320.7	c.874C>A	p.Arg292Ser	missense_variant	5/11	1		ENSP00000377855	A2
PPARGC1B	ENST00000360453.8	c.757C>A	p.Arg253Ser	missense_variant	4/11	1		ENSP00000353638	A2
PPARGC1B	ENST00000403750.5	c.682C>A	p.Arg228Ser	missense_variant	4/11	2		ENSP00000384403	A2

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11529 AN: 152090 Hom.: 746 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0726

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0690

GnomAD3 exomes AF: 0.0507 AC: 12600 AN: 248750 Hom.: 592 AF XY: 0.0494 AC XY: 6662 AN XY: 134986

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.0663

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0391 AC: 57194 AN: 1460926 Hom.: 1798 Cov.: 32 AF XY: 0.0396 AC XY: 28799 AN XY: 726744

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.0689

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0525

GnomAD4 genome AF: 0.0758 AC: 11535 AN: 152208 Hom.: 748 Cov.: 32 AF XY: 0.0746 AC XY: 5554 AN XY: 74430

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.0722

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.0328

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0389 Hom.: 426

Bravo AF: 0.0830

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.176 AC: 776

ESP6500EA AF: 0.0340 AC: 292

ExAC AF: 0.0543 AC: 6588

Asia WGS AF: 0.0970 AC: 337 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0342

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.64	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.5	.;M;M;.
MutationTaster	Benign	0.028	P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.14	T;T;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.54
MPC		0.69
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.37
gMVP		0.31

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

Other links and lift over

dbSNP: rs11959820; hg19: chr5-149212510; COSMIC: COSV58525890; COSMIC: COSV58525890;