5-149832908-G-A

Position:

• chr5-149832908-G-A

Variant summary

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

The ENST00000309241.10(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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.070 (476 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5212 hom.)
• Consequence: PPARGC1B ENST00000309241.10 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.967

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=0.0014909208).
• 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/exons	MANE	Protein	UniProt
PPARGC1B	NM_133263.4	c.835G>A	p.Val279Ile	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.835G>A	p.Val279Ile	missense_variant	5/12	1	NM_133263.4	ENSP00000312649.5
PPARGC1B	ENST00000394320.7	c.835G>A	p.Val279Ile	missense_variant	5/11	1		ENSP00000377855.3
PPARGC1B	ENST00000360453.8	c.718G>A	p.Val240Ile	missense_variant	4/11	1		ENSP00000353638.4
PPARGC1B	ENST00000403750.5	c.643G>A	p.Val215Ile	missense_variant	4/11	2		ENSP00000384403.1

Frequencies

GnomAD3 genomes AF: 0.0703 AC: 10695 AN: 152114 Hom.: 476 Cov.: 32

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

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.: 32 AF XY: 0.0812 AC XY: 59010 AN XY: 726694

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.: 32 AF XY: 0.0712 AC XY: 5303 AN XY: 74432

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.78	T
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	N
LIST_S2	Benign	0.67	T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	.;M;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs17572019; hg19: chr5-149212471;