NM_001135024.2:c.-46_-31dupCAGCGGCGCACCTGAC

Variant names:

• chr11-34916459-T-TCCAGCGGCGCACCTGA
• rs1176892497
• NM_001135024.2:c.-46_-31dupCAGCGGCGCACCTGAC

Variant summary

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

The NM_001135024.2(PDHX):​c.-46_-31dupCAGCGGCGCACCTGAC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: PDHX NM_001135024.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03
• 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 0 ACMG points.

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.-46_-31dupCAGCGGCGCACCTGAC		5_prime_UTR	Exon 1 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_003477.3	MANE Select	c.-197_-196insCCAGCGGCGCACCTGA		upstream_gene	N/A	NP_003468.2	O00330-1
	APIP	NM_015957.4	MANE Select	c.-191_-176dupTCAGGTGCGCCGCTGG		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.-46_-31dupCAGCGGCGCACCTGAC		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000937716.1		c.-191_-176dupTCAGGTGCGCCGCTGG		5_prime_UTR	Exon 1 of 7	ENSP00000607775.1
	APIP	ENST00000901544.1		c.-191_-176dupTCAGGTGCGCCGCTGG		5_prime_UTR	Exon 1 of 6	ENSP00000571603.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150874 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1310934 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 638572

African (AFR) AF: 0.0000346 AC: 1 AN: 28920

American (AMR) AF: 0.00 AC: 0 AN: 24060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19652

East Asian (EAS) AF: 0.00 AC: 0 AN: 35028

South Asian (SAS) AF: 0.00 AC: 0 AN: 66590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041112

Other (OTH) AF: 0.00 AC: 0 AN: 54234

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150874 Hom.: 0 Cov.: 33 AF XY: 0.0000272 AC XY: 2 AN XY: 73610

African (AFR) AF: 0.0000489 AC: 2 AN: 40888

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67708

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
Mutation Taster		=100/100	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1176892497; hg19: chr11-34938006;