5-149820445-G-T

Variant names:

• chr5-149820445-G-T
• rs45518035
• NM_133263.4:c.91G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133263.4(PPARGC1B):​c.91G>T​(p.Gly31Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPARGC1B NM_133263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38023135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1B	NM_133263.4	MANE Select	c.91G>T	p.Gly31Trp	missense	Exon 2 of 12	NP_573570.3
	PPARGC1B	NM_001172698.2		c.91G>T	p.Gly31Trp	missense	Exon 2 of 11	NP_001166169.1	Q86YN6-5
	PPARGC1B	NM_001172699.2		c.16G>T	p.Gly6Trp	missense	Exon 2 of 11	NP_001166170.1	Q86YN6-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1B	ENST00000309241.10	TSL:1 MANE Select	c.91G>T	p.Gly31Trp	missense	Exon 2 of 12	ENSP00000312649.5	Q86YN6-1
	PPARGC1B	ENST00000394320.7	TSL:1	c.91G>T	p.Gly31Trp	missense	Exon 2 of 11	ENSP00000377855.3	Q86YN6-3
	PPARGC1B	ENST00000360453.8	TSL:1	c.91G>T	p.Gly31Trp	missense	Exon 2 of 11	ENSP00000353638.4	Q86YN6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.38		Loss of disorder (P = 0.0089)
MVP		0.35
MPC		0.74
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.59
gMVP		0.33
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs45518035; hg19: chr5-149200008;