chr4-23814051-C-T

Position:

• chr4-23814051-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013261.5(PPARGC1A):​c.1432G>A​(p.Ala478Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.462

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06124741).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPARGC1A	NM_013261.5	c.1432G>A	p.Ala478Thr	missense_variant	8/13	ENST00000264867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPARGC1A	ENST00000264867.7	c.1432G>A	p.Ala478Thr	missense_variant	8/13	1	NM_013261.5	P1
PPARGC1A	ENST00000613098.4	c.1051G>A	p.Ala351Thr	missense_variant	7/12	1
PPARGC1A	ENST00000506055.5	c.*647G>A		3_prime_UTR_variant, NMD_transcript_variant	8/13	1
PPARGC1A	ENST00000509702.5	n.1472G>A		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461772 Hom.: 0 Cov.: 64 AF XY: 0.0000151 AC XY: 11 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.1432G>A (p.A478T) alteration is located in exon 8 (coding exon 8) of the PPARGC1A gene. This alteration results from a G to A substitution at nucleotide position 1432, causing the alanine (A) at amino acid position 478 to be replaced by a threonine (T). 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	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.13	N;.
REVEL	Benign	0.033
Sift	Benign	0.33	T;.
Sift4G	Benign	0.52	T;T
Polyphen		0.031	B;.
Vest4		0.058
MutPred		0.15		Gain of phosphorylation at A478 (P = 0.0564);.;
MVP		0.36
MPC		0.21
ClinPred		0.17	T
GERP RS		3.5
Varity_R		0.035
gMVP		0.20

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: chr4-23815674;