5-149832908-G-C

Variant names:

• chr5-149832908-G-C
• rs17572019
• NM_133263.4:c.835G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133263.4(PPARGC1B):​c.835G>C​(p.Val279Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V279I) 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: 0.967
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0643391).

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.835G>C	p.Val279Leu	missense	Exon 5 of 12	NP_573570.3
	PPARGC1B	NM_001172698.2		c.718G>C	p.Val240Leu	missense	Exon 4 of 11	NP_001166169.1	Q86YN6-5
	PPARGC1B	NM_001172699.2		c.643G>C	p.Val215Leu	missense	Exon 4 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.835G>C	p.Val279Leu	missense	Exon 5 of 12	ENSP00000312649.5	Q86YN6-1
	PPARGC1B	ENST00000394320.7	TSL:1	c.835G>C	p.Val279Leu	missense	Exon 5 of 11	ENSP00000377855.3	Q86YN6-3
	PPARGC1B	ENST00000360453.8	TSL:1	c.718G>C	p.Val240Leu	missense	Exon 4 of 11	ENSP00000353638.4	Q86YN6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726710

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52460

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.54
DANN	Benign	0.74
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.97
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.043
Sift	Benign	0.18	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.029
MutPred		0.12		Loss of catalytic residue at V279 (P = 0.193)
MVP		0.12
MPC		0.16
ClinPred		0.073	T
GERP RS		-1.7
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.086
Mutation Taster		=97/3	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: rs17572019; hg19: chr5-149212471;