11-35010029-G-A

Variant names:

• chr11-35010029-G-A
• rs952489
• XR_001748180.2:n.8944C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XR_001748180.2(LOC105376626):​n.8944C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 152,146 control chromosomes in the GnomAD database, including 28,811 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (28811 hom., cov: 32)
• Consequence: LOC105376626 XR_001748180.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 10 publications found

Genes affected

LOC105376626 (HGNC:):

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3-binding protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105376626	XR_001748180.2	n.8944C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000477173.3	n.162-10179G>A		intron_variant	Intron 2 of 2	3
ENSG00000289526	ENST00000748179.1	n.438-2176C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89827 AN: 152028 Hom.: 28825 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.605

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.590 AC: 89809 AN: 152146 Hom.: 28811 Cov.: 32 AF XY: 0.592 AC XY: 43997 AN XY: 74376

African (AFR) AF: 0.318 AC: 13203 AN: 41502

American (AMR) AF: 0.599 AC: 9160 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2475 AN: 3470

East Asian (EAS) AF: 0.751 AC: 3885 AN: 5176

South Asian (SAS) AF: 0.606 AC: 2917 AN: 4816

European-Finnish (FIN) AF: 0.688 AC: 7275 AN: 10574

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48671 AN: 67988

Other (OTH) AF: 0.599 AC: 1267 AN: 2116

Alfa AF: 0.586 Hom.: 3355

Bravo AF: 0.572

Asia WGS AF: 0.656 AC: 2283 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.67
PhyloP100		1.5

Splicing

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

Other links and lift over

dbSNP: rs952489; hg19: chr11-35031576;