NM_133263.4:c.272C>T

Variant names:

• chr5-149826692-C-T
• NM_133263.4:c.272C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133263.4(PPARGC1B):​c.272C>T​(p.Ala91Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPARGC1B NM_133263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARGC1B	NM_133263.4	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 12	ENST00000309241.10	NP_573570.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARGC1B	ENST00000309241.10	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 12	1	NM_133263.4	ENSP00000312649.5
PPARGC1B	ENST00000394320.7	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 11	1		ENSP00000377855.3
PPARGC1B	ENST00000360453.8	c.272C>T	p.Ala91Val	missense_variant	Exon 3 of 11	1		ENSP00000353638.4
PPARGC1B	ENST00000403750.5	c.197C>T	p.Ala66Val	missense_variant	Exon 3 of 11	2		ENSP00000384403.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272C>T (p.A91V) alteration is located in exon 3 (coding exon 3) of the PPARGC1B gene. This alteration results from a C to T substitution at nucleotide position 272, causing the alanine (A) at amino acid position 91 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;.;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.0	M;M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.18	T;D;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.53
MutPred		0.29		Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);Loss of disorder (P = 0.0576);.;
MVP		0.44
MPC		0.68
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149206255;