11-34916337-G-A

Variant names:

• chr11-34916337-G-A
• rs2956113
• NM_015957.4:c.-53C>T

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.-53C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,599,314 control chromosomes in the GnomAD database, including 110,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10153 hom., cov: 36)
  • Exomes 𝑓: 0.36 (100591 hom.)
• Consequence: APIP NM_015957.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08

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=-0.76).
• BP6: Variant 11-34916337-G-A is Benign according to our data. Variant chr11-34916337-G-A is described in ClinVar as [Benign]. Clinvar id is 304449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APIP	NM_015957.4	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000395787.4	NP_057041.2
APIP	NM_015957.4	c.-53C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000395787.4	NP_057041.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_015957.4	ENSP00000379133.3
APIP	ENST00000395787.4	c.-53C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_015957.4	ENSP00000379133.3

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53857 AN: 152156 Hom.: 10163 Cov.: 36

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.413 AC: 87642 AN: 212210 Hom.: 19222 AF XY: 0.414 AC XY: 48209 AN XY: 116506

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.754

Gnomad SAS exome AF: 0.482

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.365 AC: 527647 AN: 1447042 Hom.: 100591 Cov.: 48 AF XY: 0.368 AC XY: 264145 AN XY: 718580

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.416

Gnomad4 EAS exome AF: 0.725

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.341

Gnomad4 OTH exome AF: 0.376

GnomAD4 genome AF: 0.354 AC: 53844 AN: 152272 Hom.: 10153 Cov.: 36 AF XY: 0.364 AC XY: 27121 AN XY: 74456

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.339

Alfa AF: 0.284 Hom.: 1157

Bravo AF: 0.346

Asia WGS AF: 0.589 AC: 2051 AN: 3476

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	Mar 03, 2015	- -

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	-0.76
CADD	Benign	4.7
DANN	Benign	0.89
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: rs2956113; hg19: chr11-34937884;