11-34919551-C-G

Variant names:

• chr11-34919551-C-G
• rs7479823
• NM_003477.3:c.160+2736C>G

Variant summary

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

The NM_003477.3(PDHX):​c.160+2736C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,128 control chromosomes in the GnomAD database, including 4,918 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 0.22 (4918 hom., cov: 33)
• Consequence: PDHX NM_003477.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.176
• Publications: 7 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]

PDHX Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003477.3. 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_003477.3	MANE Select	c.160+2736C>G		intron	N/A	NP_003468.2	O00330-1
	PDHX	NM_001135024.2		c.-21+3065C>G		intron	N/A	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_001166158.2		c.160+2736C>G		intron	N/A	NP_001159630.1	O00330-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000227868.9	TSL:1 MANE Select	c.160+2736C>G		intron	N/A	ENSP00000227868.4	O00330-1
	PDHX	ENST00000885501.1		c.160+2736C>G		intron	N/A	ENSP00000555560.1
	PDHX	ENST00000952507.1		c.160+2736C>G		intron	N/A	ENSP00000622566.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33780 AN: 152010 Hom.: 4917 Cov.: 33

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.222 AC: 33783 AN: 152128 Hom.: 4918 Cov.: 33 AF XY: 0.214 AC XY: 15911 AN XY: 74358

African (AFR) AF: 0.0702 AC: 2915 AN: 41514

American (AMR) AF: 0.192 AC: 2935 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 873 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.128 AC: 619 AN: 4828

European-Finnish (FIN) AF: 0.241 AC: 2550 AN: 10560

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22822 AN: 67976

Other (OTH) AF: 0.230 AC: 486 AN: 2112

Alfa AF: 0.154 Hom.: 343

Bravo AF: 0.214

Asia WGS AF: 0.0600 AC: 207 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.3
DANN	Benign	0.73
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7479823; hg19: chr11-34941098;