chr8-93924304-G-C

Variant names:

• chr8-93924304-G-C
• rs911
• NM_018444.4:c.*631G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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]

PDP1 Gene-Disease associations (from GenCC):

• pyruvate dehydrogenase phosphatase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PDP1	NM_018444.4	c.*631G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000297598.5	NP_060914.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDP1	ENST00000297598.5	c.*631G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_018444.4	ENSP00000297598.4
PDP1	ENST00000520728.5	c.*631G>C		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000428317.1
PDP1	ENST00000396200.3	c.*631G>C		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000379503.3

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

African (AFR) AF: 1.00 AC: 4 AN: 4

American (AMR) AF: 0.250 AC: 3 AN: 12

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 3 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.428 AC: 6210 AN: 14522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.406 AC: 52 AN: 128

Other (OTH) AF: 0.467 AC: 43 AN: 92

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

African (AFR) AF: 0.689 AC: 28612 AN: 41502

American (AMR) AF: 0.617 AC: 9433 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1708 AN: 3470

East Asian (EAS) AF: 0.691 AC: 3587 AN: 5190

South Asian (SAS) AF: 0.496 AC: 2390 AN: 4820

European-Finnish (FIN) AF: 0.425 AC: 4488 AN: 10550

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27662 AN: 67968

Other (OTH) AF: 0.537 AC: 1128 AN: 2102

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
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs911; hg19: chr8-94936532;