NM_013261.5:c.1835C>T

Variant names:

• chr4-23813084-G-A
• rs3736265
• NM_013261.5:c.1835C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_013261.5(PPARGC1A):​c.1835C>T​(p.Thr612Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,613,862 control chromosomes in the GnomAD database, including 4,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T612P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.073 (458 hom., cov: 31)
  • Exomes 𝑓: 0.065 (4021 hom.)
• Consequence: PPARGC1A NM_013261.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.51
• Publications: 72 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014580488).
• BP6: Variant 4-23813084-G-A is Benign according to our data. Variant chr4-23813084-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056132.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

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.1835C>T	p.Thr612Met	missense	Exon 9 of 13	NP_037393.1	Q9UBK2-1
	PPARGC1A	NM_001330751.2		c.1850C>T	p.Thr617Met	missense	Exon 11 of 15	NP_001317680.1	Q9UBK2-3
	PPARGC1A	NM_001354825.2		c.1850C>T	p.Thr617Met	missense	Exon 10 of 14	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.1835C>T	p.Thr612Met	missense	Exon 9 of 13	ENSP00000264867.2	Q9UBK2-1
	PPARGC1A	ENST00000613098.4	TSL:1	c.1454C>T	p.Thr485Met	missense	Exon 8 of 12	ENSP00000481498.1	Q9UBK2-9
	PPARGC1A	ENST00000506055.5	TSL:1	n.*1050C>T		non_coding_transcript_exon	Exon 9 of 13	ENSP00000423075.1	Q9UBK2-2

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11040 AN: 152076 Hom.: 458 Cov.: 31

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0798

GnomAD2 exomes AF: 0.0860 AC: 21604 AN: 251286 AF XY: 0.0873

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0992

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0850

GnomAD4 exome AF: 0.0649 AC: 94876 AN: 1461668 Hom.: 4021 Cov.: 32 AF XY: 0.0668 AC XY: 48598 AN XY: 727152

African (AFR) AF: 0.0616 AC: 2063 AN: 33472

American (AMR) AF: 0.0973 AC: 4350 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 2169 AN: 26128

East Asian (EAS) AF: 0.194 AC: 7682 AN: 39694

South Asian (SAS) AF: 0.127 AC: 10951 AN: 86246

European-Finnish (FIN) AF: 0.104 AC: 5559 AN: 53414

Middle Eastern (MID) AF: 0.0636 AC: 367 AN: 5768

European-Non Finnish (NFE) AF: 0.0516 AC: 57418 AN: 1111836

Other (OTH) AF: 0.0715 AC: 4317 AN: 60390

GnomAD4 genome AF: 0.0725 AC: 11040 AN: 152194 Hom.: 458 Cov.: 31 AF XY: 0.0779 AC XY: 5792 AN XY: 74398

African (AFR) AF: 0.0629 AC: 2611 AN: 41524

American (AMR) AF: 0.0856 AC: 1310 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 281 AN: 3472

East Asian (EAS) AF: 0.183 AC: 946 AN: 5156

South Asian (SAS) AF: 0.145 AC: 697 AN: 4808

European-Finnish (FIN) AF: 0.104 AC: 1105 AN: 10596

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0558 AC: 3793 AN: 68020

Other (OTH) AF: 0.0784 AC: 166 AN: 2116

Alfa AF: 0.0609 Hom.: 1302

Bravo AF: 0.0689

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0514 AC: 198

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.0545 AC: 469

ExAC AF: 0.0828 AC: 10050

Asia WGS AF: 0.141 AC: 487 AN: 3478

EpiCase AF: 0.0636

EpiControl AF: 0.0609

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PPARGC1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.019	D
Polyphen		0.0	B
Vest4		0.11
MPC		0.22
ClinPred		0.0015	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.26
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3736265; hg19: chr4-23814707; COSMIC: COSV53525186; COSMIC: COSV53525186;