chr11-34916454-A-G

Position:

• chr11-34916454-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.278

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 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	c.-53A>G		5_prime_UTR_variant	1/11		NP_001128496.2
PDHX	XM_011520390.2	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	c.-53A>G		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5	c.-21+516A>G		intron_variant		4		ENSP00000431281

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28665 AN: 151474 Hom.: 3869 Cov.: 32

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

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.: 40 AF XY: 0.118 AC XY: 75583 AN XY: 639870

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.: 32 AF XY: 0.186 AC XY: 13810 AN XY: 74072

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

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	T
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	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.00067	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.0050
Sift	Benign	0.54	T
Sift4G	Benign	0.34	T
Vest4		0.025
ClinPred		0.0020	T
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

Other links and lift over

dbSNP: rs113073242; hg19: chr11-34938001; COSMIC: COSV53505903; COSMIC: COSV53505903;