chr11-34916384-G-A

Position:

• chr11-34916384-G-A

Variant summary

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

The ENST00000448838.8(PDHX):​c.-123G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,550,884 control chromosomes in the GnomAD database, including 108,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10977 hom., cov: 35)
  • Exomes 𝑓: 0.37 (97668 hom.)
• Consequence: PDHX ENST00000448838.8 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00600

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]

APIP (HGNC:17581): (APAF1 interacting protein) Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1212569E-6).
• BP6: Variant 11-34916384-G-A is Benign according to our data. Variant chr11-34916384-G-A is described in ClinVar as [Benign]. Clinvar id is 304451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-34916384-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHX	XM_011520390.2	c.-21+446G>A		intron_variant			XP_011518692.1
APIP	NM_015957.4			upstream_gene_variant		ENST00000395787.4	NP_057041.2
APIP	XM_011520154.4			upstream_gene_variant			XP_011518456.1
APIP	XM_017017875.3			upstream_gene_variant			XP_016873364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000448838.8	c.-123G>A		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5	c.-21+446G>A		intron_variant		4		ENSP00000431281
APIP	ENST00000395787.4			upstream_gene_variant		1	NM_015957.4	ENSP00000379133	P1
APIP	ENST00000527830.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56730 AN: 152108 Hom.: 10981 Cov.: 35

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.362

GnomAD3 exomes AF: 0.426 AC: 62652 AN: 147112 Hom.: 14136 AF XY: 0.428 AC XY: 34315 AN XY: 80166

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.756

Gnomad SAS exome AF: 0.482

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.366 AC: 511824 AN: 1398662 Hom.: 97668 Cov.: 45 AF XY: 0.369 AC XY: 254495 AN XY: 689798

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.724

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.373 AC: 56738 AN: 152222 Hom.: 10977 Cov.: 35 AF XY: 0.382 AC XY: 28437 AN XY: 74424

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.359

Alfa AF: 0.361 Hom.: 4977

Bravo AF: 0.368

TwinsUK AF: 0.340 AC: 1261

ALSPAC AF: 0.335 AC: 1292

ExAC AF: 0.339 AC: 34762

Asia WGS AF: 0.594 AC: 2069 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.94
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0016	P;P
PROVEAN	Benign	0.35	N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.45	T
Vest4		0.042
ClinPred		0.034	T
GERP RS		-2.4

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

Other links and lift over

dbSNP: rs2956111; hg19: chr11-34937931; COSMIC: COSV53505896; COSMIC: COSV53505896;