11-34916454-A-G

Position:

chr11-34916454-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001135024.2(PDHX):c.-53A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,465,234 control chromosomes in the GnomAD database, including 14,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3876 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10653 hom. )

Consequence

PDHX
NM_001135024.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.278

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.676316E-4).

BP6

Variant 11-34916454-A-G is Benign according to our data. Variant chr11-34916454-A-G is described in ClinVar as [Benign]. Clinvar id is 304454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-34916454-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHX	NM_001135024.2 linkuse as main transcript	c.-53A>G		5_prime_UTR_variant	1/11		NP_001128496.2
PDHX	XM_011520390.2 linkuse as main transcript	c.-21+516A>G		intron_variant			XP_011518692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000448838.8 linkuse as main transcript	c.-53A>G		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5 linkuse as main transcript	c.-21+516A>G		intron_variant		4		ENSP00000431281

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28665

AN:

151474

Hom.:

3869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0861

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.125

AC:

9758

AN:

78302

Hom.:

878

AF XY:

0.122

AC XY:

4971

AN XY:

40748

show subpopulations

Gnomad AFR exome

AF:

0.403

Gnomad AMR exome

AF:

0.0818

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.0949

Gnomad SAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.118

AC:

155343

AN:

1313648

Hom.:

10653

Cov.:

AF XY:

0.118

AC XY:

75583

AN XY:

639870

show subpopulations

Gnomad4 AFR exome

AF:

0.398

Gnomad4 AMR exome

AF:

0.0894

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.0962

Gnomad4 SAS exome

AF:

0.117

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.129

GnomAD4 genome

AF:

0.189

AC:

28705

AN:

151586

Hom.:

3876

Cov.:

AF XY:

0.186

AC XY:

13810

AN XY:

74072

show subpopulations

Gnomad4 AFR

AF:

0.391

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.0862

Gnomad4 SAS

AF:

0.115

Gnomad4 FIN

AF:

0.117

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.148

Hom.:

423

Bravo

AF:

0.199

TwinsUK

AF:

0.120

AC:

445

ALSPAC

AF:

0.115

AC:

442

ExAC

AF:

0.0415

AC:

2593

Asia WGS

AF:

0.0890

AC:

307

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyruvate dehydrogenase E3-binding protein deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.0

DANN

Benign

0.55

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00069

LIST_S2

Benign

0.17

MetaRNN

Benign

0.00067

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

P;P

PROVEAN

Benign

-0.55

REVEL

Benign

0.0050

Sift

Benign

0.54

Sift4G

Benign

0.34

Vest4

0.025

ClinPred

0.0020

GERP RS

-0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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