chr5-149820445-G-A

Position:

• chr5-149820445-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_133263.4(PPARGC1B):​c.91G>A​(p.Gly31Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,718 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (13 hom.)
• Consequence: PPARGC1B NM_133263.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.42

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=0.00728783).
• BP6: Variant 5-149820445-G-A is Benign according to our data. Variant chr5-149820445-G-A is described in ClinVar as [Benign]. Clinvar id is 780570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00624 (950/152222) while in subpopulation AFR AF= 0.0217 (902/41536). AF 95% confidence interval is 0.0205. There are 12 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 950 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1B	NM_133263.4	c.91G>A	p.Gly31Arg	missense_variant	2/12	ENST00000309241.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1B	ENST00000309241.10	c.91G>A	p.Gly31Arg	missense_variant	2/12	1	NM_133263.4	P2
PPARGC1B	ENST00000394320.7	c.91G>A	p.Gly31Arg	missense_variant	2/11	1		A2
PPARGC1B	ENST00000360453.8	c.91G>A	p.Gly31Arg	missense_variant	2/11	1		A2
PPARGC1B	ENST00000403750.5	c.16G>A	p.Gly6Arg	missense_variant	2/11	2		A2

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 944 AN: 152104 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00167 AC: 418 AN: 251014 Hom.: 6 AF XY: 0.00119 AC XY: 162 AN XY: 135664

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000675 AC: 987 AN: 1461496 Hom.: 13 Cov.: 30 AF XY: 0.000598 AC XY: 435 AN XY: 727084

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152222 Hom.: 12 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74418

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00739

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	.;.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;T;T;T
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.39
MutPred		0.32		Loss of glycosylation at S30 (P = 0.038);Loss of glycosylation at S30 (P = 0.038);Loss of glycosylation at S30 (P = 0.038);.;
MVP		0.36
MPC		0.68
ClinPred		0.033	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.45
gMVP		0.32

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: rs45518035; hg19: chr5-149200008; COSMIC: COSV58530252; COSMIC: COSV58530252;