5-149730416-C-T

Variant names:

• chr5-149730416-C-T
• rs369401772
• NM_133263.4:c.74C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133263.4(PPARGC1B):​c.74C>T​(p.Thr25Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,404,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. T25K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PPARGC1B NM_133263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20670256).

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.74C>T	p.Thr25Met	missense	Exon 1 of 12	NP_573570.3
	PPARGC1B	NM_001172698.2		c.74C>T	p.Thr25Met	missense	Exon 1 of 11	NP_001166169.1	Q86YN6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1B	ENST00000309241.10	TSL:1 MANE Select	c.74C>T	p.Thr25Met	missense	Exon 1 of 12	ENSP00000312649.5	Q86YN6-1
	PPARGC1B	ENST00000394320.7	TSL:1	c.74C>T	p.Thr25Met	missense	Exon 1 of 11	ENSP00000377855.3	Q86YN6-3
	PPARGC1B	ENST00000360453.8	TSL:1	c.74C>T	p.Thr25Met	missense	Exon 1 of 11	ENSP00000353638.4	Q86YN6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1404778 Hom.: 0 Cov.: 30 AF XY: 0.00000575 AC XY: 4 AN XY: 695904

African (AFR) AF: 0.00 AC: 0 AN: 29540

American (AMR) AF: 0.00 AC: 0 AN: 37826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24724

East Asian (EAS) AF: 0.00 AC: 0 AN: 34656

South Asian (SAS) AF: 0.00 AC: 0 AN: 78598

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085800

Other (OTH) AF: 0.00 AC: 0 AN: 58086

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.000020
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.088
Sift	Benign	0.064	T
Sift4G	Benign	0.071	T
Polyphen		0.66	P
Vest4		0.38
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0522)
MVP		0.17
MPC		0.56
ClinPred		0.58	D
GERP RS		2.7
PromoterAI		-0.088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.17
Mutation Taster		=82/18	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: rs369401772; hg19: chr5-149109979;