rs387906998

chr11-34916699-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 4.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHX	NM_003477.3	c.44G>A	p.Arg15His	missense_variant	1/11	ENST00000227868.9
PDHX	NM_001166158.2	c.44G>A	p.Arg15His	missense_variant	1/6
PDHX	NM_001135024.2	c.-21+213G>A		intron_variant
PDHX	XM_011520390.2	c.-21+761G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHX	ENST00000227868.9	c.44G>A	p.Arg15His	missense_variant	1/11	1	NM_003477.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152192 Hom.: 1 Cov.: 33

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.: 0 AF XY: 0.000726 AC XY: 98 AN XY: 135078

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.: 2 Cov.: 59 AF XY: 0.000390 AC XY: 283 AN XY: 726554

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: 19 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74476

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: 65

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyruvate dehydrogenase E3-binding protein deficiency Pathogenic:1 Uncertain: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:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	This variant is associated with the following publications: (PMID: 21937992) -

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	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.55	T
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	T
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

Other links and lift over

dbSNP: rs387906998; hg19: chr11-34938246;