Variant rs202246074 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_017990.5(PDPR):c.1360G>A(p.Gly454Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G454C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 45)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

PDPR
NM_017990.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.59

Variant links:

Genes affected

PDPR (HGNC:30264): (pyruvate dehydrogenase phosphatase regulatory subunit) Pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate and links glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. The dephosphorylation and reactivation of PDC is catalyzed by pyruvate dehydrogenase phosphatase (PDP). The dimeric PDP has a catalytic subunit and a regulatory subunit. This gene encodes the FAD-containing regulatory subunit of PDP. The encoded protein acts to decrease the sensitivity of the PDP catalytic subunit to magnesium ions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

PDPR links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-70142278-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDPR	NM_017990.5 linkuse as main transcript	c.1360G>A	p.Gly454Ser	missense_variant	12/19	ENST00000288050.9	NP_060460.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDPR	ENST00000288050.9 linkuse as main transcript	c.1360G>A	p.Gly454Ser	missense_variant	12/19	1	NM_017990.5	ENSP00000288050	P1	Q8NCN5-1
	ENST00000671539.1 linkuse as main transcript	n.892-3042C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000682

AC:

AN:

249216

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135204

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

ExAC

AF:

0.0000662

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

T;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

-0.043

MutationAssessor

Benign

2.0

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.68

Sift

Benign

0.066

T;T;T

Sift4G

Benign

0.065

T;D;T

Polyphen

1.0

D;.;D

Vest4

0.93

MVP

0.90

MPC

1.2

ClinPred

0.53

GERP RS

5.2

Varity_R

0.33

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over