11-34916699-G-A

Position:

chr11-34916699-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_003477.3(PDHX):c.44G>A(p.Arg15His) variant causes a missense change. The variant allele was found at a frequency of 0.00025 in 1,612,796 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

PDHX
NM_003477.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 4.22

Variant links:

Genes affected

PDHX (HGNC:21350): (pyruvate dehydrogenase complex component X) The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

PDHX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014390051).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000125 (19/152310) while in subpopulation SAS AF= 0.00352 (17/4828). AF 95% confidence interval is 0.00224. There are 1 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHX	NM_003477.3 linkuse as main transcript	c.44G>A	p.Arg15His	missense_variant	1/11	ENST00000227868.9	NP_003468.2	O00330-1
PDHX	NM_001166158.2 linkuse as main transcript	c.44G>A	p.Arg15His	missense_variant	1/6		NP_001159630.1	O00330-2
PDHX	NM_001135024.2 linkuse as main transcript	c.-21+213G>A		intron_variant			NP_001128496.2	O00330
PDHX	XM_011520390.2 linkuse as main transcript	c.-21+761G>A		intron_variant			XP_011518692.1	A0A8C8MSB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000227868.9 linkuse as main transcript	c.44G>A	p.Arg15His	missense_variant	1/11	1	NM_003477.3	ENSP00000227868.4		O00330-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000554

AC:

138

AN:

248950

Hom.:

AF XY:

0.000726

AC XY:

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00405

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000263

AC:

384

AN:

1460486

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

283

AN XY:

726554

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.0000570

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000125

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Bravo

AF:

0.0000302

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E3-binding protein deficiency

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2011	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	This variant is associated with the following publications: (PMID: 21937992) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 15 of the PDHX protein (p.Arg15His). This variant is present in population databases (rs387906998, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 21937992). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30752). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 10, 2023

Variant summary: PDHX c.44G>A (p.Arg15His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 248950 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PDHX causing Pyruvate Dehydrogenase E3-Binding Protein Deficiency (0.00055 vs 0.0011), allowing no conclusion about variant significance. c.44G>A has been reported in the literature in a family affected with intellectual disability (example: Najmabadi_2011). This report does not provide unequivocal conclusions about association of the variant with Pyruvate Dehydrogenase E3-Binding Protein Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21937992). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;.

Eigen

Benign

0.020

Eigen_PC

Benign

-0.013

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.021

B;.;.

Vest4

0.55

MutPred

0.76

Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);Loss of MoRF binding (P = 0.0079);

MVP

0.60

MPC

0.24

ClinPred

0.081

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over