11-34916151-G-A

Position:

• chr11-34916151-G-A

Variant summary

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

The ENST00000395787.4(APIP):​c.57+77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,545,654 control chromosomes in the GnomAD database, including 15,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3904 hom., cov: 35)
  • Exomes 𝑓: 0.12 (11479 hom.)
• Consequence: APIP ENST00000395787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0120

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=-0.78).
• BP6: Variant 11-34916151-G-A is Benign according to our data. Variant chr11-34916151-G-A is described in ClinVar as [Benign]. Clinvar id is 304444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APIP	NM_015957.4	c.57+77C>T		intron_variant		ENST00000395787.4	NP_057041.2
APIP	XM_011520154.4	c.13+77C>T		intron_variant			XP_011518456.1
PDHX	XM_011520390.2	c.-21+213G>A		intron_variant			XP_011518692.1
APIP	XM_017017875.3	c.-301+77C>T		intron_variant			XP_016873364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4	c.57+77C>T		intron_variant		1	NM_015957.4	ENSP00000379133	P1
PDHX	ENST00000448838.8	c.-356G>A		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5	c.-21+213G>A		intron_variant		4		ENSP00000431281
APIP	ENST00000527830.1	n.124+77C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28777 AN: 152050 Hom.: 3897 Cov.: 35

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.119 AC: 165695 AN: 1393486 Hom.: 11479 Cov.: 33 AF XY: 0.119 AC XY: 81852 AN XY: 688866

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.0845

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.0972

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.189 AC: 28818 AN: 152168 Hom.: 3904 Cov.: 35 AF XY: 0.186 AC XY: 13870 AN XY: 74408

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0869

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.176

Alfa AF: 0.0694 Hom.: 96

Bravo AF: 0.199

Asia WGS AF: 0.0900 AC: 311 AN: 3478

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	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyruvate dehydrogenase E3-binding protein deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.78
CADD	Benign	7.8
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16926448; hg19: chr11-34937698;