chr11-34916458-AT-A

Variant names:

• chr11-34916458-AT-A
• rs1158194122
• NM_001135024.2:c.-48delT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001135024.2(PDHX):​c.-48delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,462,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: PDHX NM_001135024.2 5_prime_UTR
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -2.04
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-34916458-AT-A is Pathogenic according to our data. Variant chr11-34916458-AT-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 590822.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135024.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	NM_001135024.2		c.-48delT		5_prime_UTR	Exon 1 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_003477.3	MANE Select	c.-197delT		upstream_gene	N/A	NP_003468.2	O00330-1
	APIP	NM_015957.4	MANE Select	c.-175delA		upstream_gene	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000448838.8	TSL:5	c.-48delT		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000937716.1		c.-175delA		5_prime_UTR	Exon 1 of 7	ENSP00000607775.1
	APIP	ENST00000901544.1		c.-175delA		5_prime_UTR	Exon 1 of 6	ENSP00000571603.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151416 Hom.: 0 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: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000257 AC: 2 AN: 77966 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1311322 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 638810

African (AFR) AF: 0.00 AC: 0 AN: 28906

American (AMR) AF: 0.00 AC: 0 AN: 24046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19646

East Asian (EAS) AF: 0.0000571 AC: 2 AN: 35036

South Asian (SAS) AF: 0.00 AC: 0 AN: 66600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041262

Other (OTH) AF: 0.0000184 AC: 1 AN: 54266

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151416 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73948

African (AFR) AF: 0.00 AC: 0 AN: 41124

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=93/107	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1158194122; hg19: chr11-34938005;