rs7732671

Positions:

• chr5-149832680-G-C

Variant summary

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

The ENST00000309241.10(PPARGC1B):​c.607G>C​(p.Ala203Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0871 in 1,547,582 control chromosomes in the GnomAD database, including 6,416 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 (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1015 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5401 hom.)
• Consequence: PPARGC1B ENST00000309241.10 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.132

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=0.0012690127).
• BP6: Variant 5-149832680-G-C is Benign according to our data. Variant chr5-149832680-G-C is described in ClinVar as [Benign]. Clinvar id is 2039.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPARGC1B	NM_133263.4	c.607G>C	p.Ala203Pro	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.607G>C	p.Ala203Pro	missense_variant	5/12	1	NM_133263.4	ENSP00000312649	P2
PPARGC1B	ENST00000394320.7	c.607G>C	p.Ala203Pro	missense_variant	5/11	1		ENSP00000377855	A2
PPARGC1B	ENST00000360453.8	c.490G>C	p.Ala164Pro	missense_variant	4/11	1		ENSP00000353638	A2
PPARGC1B	ENST00000403750.5	c.415G>C	p.Ala139Pro	missense_variant	4/11	2		ENSP00000384403	A2

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16510 AN: 152060 Hom.: 1009 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.0939 AC: 19531 AN: 207962 Hom.: 1122 AF XY: 0.0905 AC XY: 10043 AN XY: 110986

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.0640

Gnomad SAS exome AF: 0.0668

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0836

Gnomad OTH exome AF: 0.0859

GnomAD4 exome AF: 0.0848 AC: 118292 AN: 1395404 Hom.: 5401 Cov.: 31 AF XY: 0.0840 AC XY: 57570 AN XY: 685398

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0580

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.0498

Gnomad4 NFE exome AF: 0.0825

Gnomad4 OTH exome AF: 0.0924

GnomAD4 genome AF: 0.109 AC: 16545 AN: 152178 Hom.: 1015 Cov.: 32 AF XY: 0.109 AC XY: 8134 AN XY: 74388

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0598

Gnomad4 SAS AF: 0.0613

Gnomad4 FIN AF: 0.0462

Gnomad4 NFE AF: 0.0804

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0910 Hom.: 476

Bravo AF: 0.119

TwinsUK AF: 0.0774 AC: 287

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.161 AC: 708

ESP6500EA AF: 0.0841 AC: 723

ExAC AF: 0.0916 AC: 11106

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 15863669, 19653005, 16704985) -

PPARGC1B polymorphism Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.19
DEOGEN2	Benign	0.083	.;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.51	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	.;L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.030	N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.10
MPC		0.21
ClinPred		0.0026	T
GERP RS		-4.3
Varity_R		0.050
gMVP		0.073

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: rs7732671; hg19: chr5-149212243; COSMIC: COSV58528090; COSMIC: COSV58528090;