NM_013261.5:c.1444G>C

Variant names:

• chr4-23814039-C-G
• rs8192678
• NM_013261.5:c.1444G>C

Variant summary

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

The NM_013261.5(PPARGC1A):​c.1444G>C​(p.Gly482Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. G482S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

Genes affected

PPARGC1A (HGNC:9237): (PPARG coactivator 1 alpha) The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with PPARgamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity. [provided by RefSeq, Jul 2008]

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=0.06643617).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013261.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	NM_013261.5	MANE Select	c.1444G>C	p.Gly482Arg	missense	Exon 8 of 13	NP_037393.1
	PPARGC1A	NM_001330751.2		c.1459G>C	p.Gly487Arg	missense	Exon 10 of 15	NP_001317680.1
	PPARGC1A	NM_001354825.2		c.1459G>C	p.Gly487Arg	missense	Exon 9 of 14	NP_001341754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.1444G>C	p.Gly482Arg	missense	Exon 8 of 13	ENSP00000264867.2
	PPARGC1A	ENST00000613098.4	TSL:1	c.1063G>C	p.Gly355Arg	missense	Exon 7 of 12	ENSP00000481498.1
	PPARGC1A	ENST00000506055.5	TSL:1	n.*659G>C		non_coding_transcript_exon	Exon 8 of 13	ENSP00000423075.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		2.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.059
Sift	Benign	0.46	T
Sift4G	Benign	0.17	T
Polyphen		0.041	B
Vest4		0.10
MutPred		0.17		Gain of solvent accessibility (P = 0.0128)
MVP		0.23
MPC		0.26
ClinPred		0.17	T
GERP RS		6.0
Varity_R		0.038
gMVP		0.13
Mutation Taster		=89/11	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: rs8192678; hg19: chr4-23815662;