11-34915939-G-C

Position:

• chr11-34915939-G-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+289C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 525,116 control chromosomes in the GnomAD database, including 7,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3908 hom., cov: 33)
  • Exomes 𝑓: 0.12 (3314 hom.)
• Consequence: APIP NM_015957.4 intron
• Scores: Splicing: ADA: 0.00006474
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.06

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=-0.88).
• BP6: Variant 11-34915939-G-C is Benign according to our data. Variant chr11-34915939-G-C is described in ClinVar as [Benign]. Clinvar id is 683422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APIP	NM_015957.4	c.57+289C>G		intron_variant		ENST00000395787.4
PDHX	XM_011520390.2	c.-21+1G>C		splice_donor_variant
APIP	XM_011520154.4	c.13+289C>G		intron_variant
APIP	XM_017017875.3	c.-301+289C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APIP	ENST00000395787.4	c.57+289C>G		intron_variant		1	NM_015957.4	P1
PDHX	ENST00000533550.5	c.-21+1G>C		splice_donor_variant		4
APIP	ENST00000527830.1	n.124+289C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28793 AN: 152094 Hom.: 3901 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.124 AC: 46102 AN: 372904 Hom.: 3314 Cov.: 2 AF XY: 0.124 AC XY: 24161 AN XY: 195568

Gnomad4 AFR exome AF: 0.389

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.189 AC: 28834 AN: 152212 Hom.: 3908 Cov.: 33 AF XY: 0.186 AC XY: 13884 AN XY: 74446

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0868

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.176

Alfa AF: 0.157 Hom.: 340

Bravo AF: 0.199

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.0
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: rs3763930; hg19: chr11-34937486;