11-34916150-T-C

Position:

• chr11-34916150-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015957.4(APIP):​c.57+78A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 1,543,634 control chromosomes in the GnomAD database, including 487,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47695 hom., cov: 34)
  • Exomes 𝑓: 0.79 (439917 hom.)
• Consequence: APIP NM_015957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.69

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-34916150-T-C is Benign according to our data. Variant chr11-34916150-T-C is described in ClinVar as [Benign]. Clinvar id is 304443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APIP	NM_015957.4	c.57+78A>G		intron_variant		ENST00000395787.4
APIP	XM_011520154.4	c.13+78A>G		intron_variant
PDHX	XM_011520390.2	c.-21+212T>C		intron_variant
APIP	XM_017017875.3	c.-301+78A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APIP	ENST00000395787.4	c.57+78A>G		intron_variant		1	NM_015957.4	P1
PDHX	ENST00000448838.8	c.-357T>C		5_prime_UTR_variant	1/11	5
PDHX	ENST00000533550.5	c.-21+212T>C		intron_variant		4
APIP	ENST00000527830.1	n.124+78A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.791 AC: 120209 AN: 152060 Hom.: 47674 Cov.: 34

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.775

GnomAD4 exome AF: 0.794 AC: 1105020 AN: 1391456 Hom.: 439917 Cov.: 29 AF XY: 0.793 AC XY: 545101 AN XY: 687690

Gnomad4 AFR exome AF: 0.802

Gnomad4 AMR exome AF: 0.642

Gnomad4 ASJ exome AF: 0.834

Gnomad4 EAS exome AF: 0.821

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.770

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.796

GnomAD4 genome AF: 0.790 AC: 120272 AN: 152178 Hom.: 47695 Cov.: 34 AF XY: 0.788 AC XY: 58640 AN XY: 74376

Gnomad4 AFR AF: 0.802

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.801

Gnomad4 OTH AF: 0.767

Alfa AF: 0.744 Hom.: 2241

Bravo AF: 0.788

Asia WGS AF: 0.750 AC: 2606 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Pyruvate dehydrogenase E3-binding protein deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs2016814; hg19: chr11-34937697;