rs911

Positions:

• chr8-93924304-G-C
• chr8-93924304-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018444.4(PDP1):​c.*631G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 166,862 control chromosomes in the GnomAD database, including 23,486 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (22124 hom., cov: 33)
  • Exomes 𝑓: 0.43 (1362 hom.)
• Consequence: PDP1 NM_018444.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39

Genes affected

PDP1 (HGNC:9279): (pyruvate dehydrogenase phosphatase catalytic subunit 1) Pyruvate dehydrogenase (E1) is one of the three components (E1, E2, and E3) of the large pyruvate dehydrogenase complex. Pyruvate dehydrogenase kinases catalyze phosphorylation of serine residues of E1 to inactivate the E1 component and inhibit the complex. Pyruvate dehydrogenase phosphatases catalyze the dephosphorylation and activation of the E1 component to reverse the effects of pyruvate dehydrogenase kinases. Pyruvate dehydrogenase phosphatase is a heterodimer consisting of catalytic and regulatory subunits. Two catalytic subunits have been reported; one is predominantly expressed in skeletal muscle and another one is is much more abundant in the liver. The catalytic subunit, encoded by this gene, is the former, and belongs to the protein phosphatase 2C (PP2C) superfamily. Along with the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinases, this enzyme is located in the mitochondrial matrix. Mutation in this gene causes pyruvate dehydrogenase phosphatase deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDP1	NM_018444.4	c.*631G>C		3_prime_UTR_variant	2/2	ENST00000297598.5	NP_060914.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDP1	ENST00000297598.5	c.*631G>C		3_prime_UTR_variant	2/2	1	NM_018444.4	ENSP00000297598	P4
PDP1	ENST00000520728.5	c.*631G>C		3_prime_UTR_variant	3/3	1		ENSP00000428317	P4
PDP1	ENST00000396200.3	c.*631G>C		3_prime_UTR_variant	3/3	4		ENSP00000379503	A1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79411 AN: 151978 Hom.: 22069 Cov.: 33

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.531

GnomAD4 exome AF: 0.428 AC: 6315 AN: 14766 Hom.: 1362 Cov.: 0 AF XY: 0.424 AC XY: 2978 AN XY: 7024

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.250

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.523 AC: 79530 AN: 152096 Hom.: 22124 Cov.: 33 AF XY: 0.526 AC XY: 39099 AN XY: 74346

Gnomad4 AFR AF: 0.689

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.691

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.537

Alfa AF: 0.326 Hom.: 882

Bravo AF: 0.547

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.75

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

LitVar

Other links and lift over

dbSNP: rs911; hg19: chr8-94936532;