4-23801854-AC-GT

Variant names:

• chr4-23801854-AC-GT
• NM_013261.5:c.2168_2169delGTinsAC
• PPARGC1A p.Arg723His

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_013261.5(PPARGC1A):​c.2168_2169delGTinsAC​(p.Arg723His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	NM_013261.5	MANE Select	c.2168_2169delGTinsAC	p.Arg723His	missense	N/A	NP_037393.1	Q9UBK2-1
	PPARGC1A	NM_001330751.2		c.2183_2184delGTinsAC	p.Arg728His	missense	N/A	NP_001317680.1	Q9UBK2-3
	PPARGC1A	NM_001354825.2		c.2183_2184delGTinsAC	p.Arg728His	missense	N/A	NP_001341754.1	Q9UBK2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.2168_2169delGTinsAC	p.Arg723His	missense	N/A	ENSP00000264867.2	Q9UBK2-1
	PPARGC1A	ENST00000613098.4	TSL:1	c.1787_1788delGTinsAC	p.Arg596His	missense	N/A	ENSP00000481498.1	Q9UBK2-9
	PPARGC1A	ENST00000506055.5	TSL:1	n.*1383_*1384delGTinsAC		non_coding_transcript_exon	Exon 12 of 13	ENSP00000423075.1	Q9UBK2-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-23803477;