11-34916354-A-G

Position:

• chr11-34916354-A-G

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.-70T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 1,585,520 control chromosomes in the GnomAD database, including 498,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46804 hom., cov: 36)
  • Exomes 𝑓: 0.79 (451838 hom.)
• Consequence: APIP NM_015957.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -3.83

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=-0.9).
• BP6: Variant 11-34916354-A-G is Benign according to our data. Variant chr11-34916354-A-G is described in ClinVar as [Benign]. Clinvar id is 304450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-34916354-A-G is described in Lovd as [Benign].
• 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	Protein	UniProt
APIP	NM_015957.4	c.-70T>C		5_prime_UTR_variant	1/7	ENST00000395787.4	NP_057041.2
APIP	XM_011520154.4	c.-114T>C		5_prime_UTR_variant	1/8		XP_011518456.1
APIP	XM_017017875.3	c.-427T>C		5_prime_UTR_variant	1/8		XP_016873364.1
PDHX	XM_011520390.2	c.-21+416A>G		intron_variant			XP_011518692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4	c.-70T>C		5_prime_UTR_variant	1/7	1	NM_015957.4	ENSP00000379133	P1
PDHX	ENST00000448838.8	c.-153A>G		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5	c.-21+416A>G		intron_variant		4		ENSP00000431281
APIP	ENST00000527830.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119126 AN: 152154 Hom.: 46789 Cov.: 36

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.773

GnomAD3 exomes AF: 0.768 AC: 147964 AN: 192750 Hom.: 57161 AF XY: 0.773 AC XY: 81762 AN XY: 105796

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.832

Gnomad EAS exome AF: 0.849

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.774

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.771

GnomAD4 exome AF: 0.793 AC: 1136521 AN: 1433250 Hom.: 451838 Cov.: 49 AF XY: 0.792 AC XY: 562554 AN XY: 710446

Gnomad4 AFR exome AF: 0.774

Gnomad4 AMR exome AF: 0.637

Gnomad4 ASJ exome AF: 0.834

Gnomad4 EAS exome AF: 0.823

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.772

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.783 AC: 119181 AN: 152270 Hom.: 46804 Cov.: 36 AF XY: 0.781 AC XY: 58145 AN XY: 74442

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.801

Gnomad4 OTH AF: 0.765

Alfa AF: 0.796 Hom.: 11407

Bravo AF: 0.779

Asia WGS AF: 0.744 AC: 2588 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	in vitro	Seelig Lab, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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 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	-0.90
CADD	Benign	1.8
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs2956112; hg19: chr11-34937901;