rs555380381

Variant names:

• chr11-34916448-C-G
• rs555380381
• NM_001135024.2:c.-59C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-34916448-C-G
• chr11-34916448-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001135024.2(PDHX):​c.-59C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000136 in 1,468,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: PDHX NM_001135024.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.32
• Publications: 0 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]

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]

ACMG classification

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 (MetaRNN=0.05470243).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	NM_001135024.2		c.-59C>G		5_prime_UTR	Exon 1 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_003477.3	MANE Select	c.-208C>G		upstream_gene	N/A	NP_003468.2	O00330-1
	APIP	NM_015957.4	MANE Select	c.-164G>C		upstream_gene	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000448838.8	TSL:5	c.-59C>G		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000937716.1		c.-164G>C		5_prime_UTR	Exon 1 of 7	ENSP00000607775.1
	APIP	ENST00000901544.1		c.-164G>C		5_prime_UTR	Exon 1 of 6	ENSP00000571603.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151746 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 1 AN: 78270 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000718

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.59e-7 AC: 1 AN: 1316680 Hom.: 0 Cov.: 41 AF XY: 0.00000156 AC XY: 1 AN XY: 641842

African (AFR) AF: 0.00 AC: 0 AN: 29074

American (AMR) AF: 0.0000409 AC: 1 AN: 24430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19890

East Asian (EAS) AF: 0.00 AC: 0 AN: 35082

South Asian (SAS) AF: 0.00 AC: 0 AN: 67206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043120

Other (OTH) AF: 0.00 AC: 0 AN: 54360

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151746 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74108

African (AFR) AF: 0.00 AC: 0 AN: 41294

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.23
DANN	Benign	0.54
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.97	T
PhyloP100		-3.3
PROVEAN	Benign	0.67	N
REVEL	Benign	0.012
Sift	Benign	0.097	T
Sift4G	Benign	0.13	T
Vest4		0.094
MutPred		0.30		Gain of MoRF binding (P = 0.005)
MVP		0.061
ClinPred		0.14	T
GERP RS		-8.2
PromoterAI		0.0051	Neutral

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: rs555380381; hg19: chr11-34937995;