rs61752925

Variant names:

• chr11-34960443-G-A
• rs61752925
• NM_003477.3:c.566G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-34960443-G-A
• chr11-34960443-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003477.3(PDHX):​c.566G>A​(p.Arg189His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,612,678 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0062 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: PDHX NM_003477.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.13
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01023978).
• BP6: Variant 11-34960443-G-A is Benign according to our data. Variant chr11-34960443-G-A is described in ClinVar as Benign. ClinVar VariationId is 138661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00618 (940/152052) while in subpopulation AFR AF = 0.0217 (901/41462). AF 95% confidence interval is 0.0206. There are 12 homozygotes in GnomAd4. There are 454 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.566G>A	p.Arg189His	missense	Exon 5 of 11	NP_003468.2	O00330-1
	PDHX	NM_001135024.2		c.386G>A	p.Arg129His	missense	Exon 5 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_001166158.2		c.342+12837G>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.566G>A	p.Arg189His	missense	Exon 5 of 11	ENSP00000227868.4	O00330-1
	PDHX	ENST00000885501.1		c.566G>A	p.Arg189His	missense	Exon 5 of 12	ENSP00000555560.1
	PDHX	ENST00000952507.1		c.566G>A	p.Arg189His	missense	Exon 5 of 11	ENSP00000622566.1

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 938 AN: 151936 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00144 AC: 361 AN: 251302 AF XY: 0.00117

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000661 AC: 966 AN: 1460626 Hom.: 8 Cov.: 29 AF XY: 0.000568 AC XY: 413 AN XY: 726662

African (AFR) AF: 0.0232 AC: 775 AN: 33428

American (AMR) AF: 0.000716 AC: 32 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39584

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111124

Other (OTH) AF: 0.00124 AC: 75 AN: 60328

GnomAD4 genome AF: 0.00618 AC: 940 AN: 152052 Hom.: 12 Cov.: 32 AF XY: 0.00611 AC XY: 454 AN XY: 74326

African (AFR) AF: 0.0217 AC: 901 AN: 41462

American (AMR) AF: 0.00164 AC: 25 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67984

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00497 Hom.: 719

Bravo AF: 0.00629

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.81
MPC		0.33
ClinPred		0.061	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.79
Mutation Taster		=69/31	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: rs61752925; hg19: chr11-34981990; COSMIC: COSV57163949;