chr11-34960466-C-A

Variant names:

• chr11-34960466-C-A
• rs139052284
• NM_003477.3:c.589C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003477.3(PDHX):​c.589C>A​(p.Leu197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PDHX NM_003477.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.34
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009708434).
• BP6: Variant 11-34960466-C-A is Benign according to our data. Variant chr11-34960466-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214960.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00126 (192/152262) while in subpopulation AFR AF = 0.00423 (176/41566). AF 95% confidence interval is 0.00372. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.589C>A	p.Leu197Met	missense	Exon 5 of 11	NP_003468.2	O00330-1
	PDHX	NM_001135024.2		c.409C>A	p.Leu137Met	missense	Exon 5 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_001166158.2		c.342+12860C>A		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.589C>A	p.Leu197Met	missense	Exon 5 of 11	ENSP00000227868.4	O00330-1
	PDHX	ENST00000885501.1		c.589C>A	p.Leu197Met	missense	Exon 5 of 12	ENSP00000555560.1
	PDHX	ENST00000952507.1		c.589C>A	p.Leu197Met	missense	Exon 5 of 11	ENSP00000622566.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000434 AC: 109 AN: 251344 AF XY: 0.000353

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1461248 Hom.: 1 Cov.: 29 AF XY: 0.000105 AC XY: 76 AN XY: 726956

African (AFR) AF: 0.00308 AC: 103 AN: 33444

American (AMR) AF: 0.000827 AC: 37 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111614

Other (OTH) AF: 0.000282 AC: 17 AN: 60368

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74438

African (AFR) AF: 0.00423 AC: 176 AN: 41566

American (AMR) AF: 0.000720 AC: 11 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	3	-	Pyruvate dehydrogenase E3-binding protein deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.39
MPC		0.29
ClinPred		0.052	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.51
Mutation Taster		=65/35	polymorphism

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: rs139052284; hg19: chr11-34982013;