rs952489

Positions:

• chr11-35010029-G-A
• chr11-35010029-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
LOC105376626	XR_001748180.2	n.8944C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000477173.3	n.162-10179G>A		intron_variant		3

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

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.713

Gnomad4 EAS AF: 0.751

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.716

Gnomad4 OTH AF: 0.599

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs952489; hg19: chr11-35031576;