Genetic Variant PPARGC1A:c.2019+3723G>C (chr4-23809024-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_013261.5(PPARGC1A):c.2019+3723G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Consequence

PPARGC1A
NM_013261.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.389

Publications

17 publications found

Variant links:

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]

PPARGC1A links:

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new If you want to explore the variant's impact on the transcript NM_013261.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 points.

PM2

Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: unknown) (threshold 0.001) — PM2 moderate.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPARGC1A	NM_013261.5	MANE Select	c.2019+3723G>C	intron	N/A	NP_037393.1	Q9UBK2-1
PPARGC1A	NM_001330751.2		c.2034+3723G>C	intron	N/A	NP_001317680.1	Q9UBK2-3
PPARGC1A	NM_001354825.2		c.2034+3723G>C	intron	N/A	NP_001341754.1	Q9UBK2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPARGC1A	ENST00000264867.7	TSL:1 MANE Select	c.2019+3723G>C	intron	N/A	ENSP00000264867.2	Q9UBK2-1
PPARGC1A	ENST00000613098.4	TSL:1	c.1638+3723G>C	intron	N/A	ENSP00000481498.1	Q9UBK2-9
PPARGC1A	ENST00000506055.5	TSL:1	n.*1234+3723G>C	intron	N/A	ENSP00000423075.1	Q9UBK2-2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000228

AC:

AN:

122680

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.43

(source)

DANN

Benign

0.32

PhyloP100

-0.39

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over