rs759318998

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001135024.2(PDHX):c.-21+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000757 in 1,439,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

PDHX
NM_001135024.2 splice_region, intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.671

Publications

0 publications found

Variant links:

Genes affected

APIP (HGNC:17581): (APAF1 interacting protein) Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

APIP links:

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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

PDHX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135024.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHX	NM_001135024.2		c.-21+8C>A	splice_region intron	N/A	NP_001128496.2	A0A8C8MSB2
PDHX	NM_003477.3	MANE Select	c.-162C>A	upstream_gene	N/A	NP_003468.2	O00330-1
APIP	NM_015957.4	MANE Select	c.-210G>T	upstream_gene	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APIP	ENST00000901544.1		c.-210G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000571603.1
APIP	ENST00000901544.1		c.-210G>T	5_prime_UTR	Exon 1 of 6	ENSP00000571603.1
PDHX	ENST00000448838.8	TSL:5	c.-21+8C>A	splice_region intron	N/A	ENSP00000389404.3	A0A8C8MSB2

Frequencies

GnomAD3 genomes

AF:

0.0000742

AC:

AN:

148266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00262

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000170

AC:

AN:

82502

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00478

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000405

GnomAD4 exome

AF:

0.0000759

AC:

AN:

1291638

Hom.:

Cov.:

AF XY:

0.0000858

AC XY:

AN XY:

629544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28986

American (AMR)

AF:

0.00

AC:

AN:

25886

Ashkenazi Jewish (ASJ)

AF:

0.00348

AC:

AN:

19810

East Asian (EAS)

AF:

0.00

AC:

AN:

34938

South Asian (SAS)

AF:

0.00

AC:

AN:

67194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4394

European-Non Finnish (NFE)

AF:

0.0000186

AC:

AN:

1023364

Other (OTH)

AF:

0.000186

AC:

AN:

53802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000742

AC:

AN:

148266

Hom.:

Cov.:

AF XY:

0.0000968

AC XY:

AN XY:

72316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39206

American (AMR)

AF:

0.00

AC:

AN:

15074

Ashkenazi Jewish (ASJ)

AF:

0.00262

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5070

South Asian (SAS)

AF:

0.00

AC:

AN:

4662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

67346

Other (OTH)

AF:

0.00

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.0000793

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E3-binding protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.67

PromoterAI

-0.10

Neutral

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over