11-34916054-A-T

Position:

• chr11-34916054-A-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.57+174T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 808,988 control chromosomes in the GnomAD database, including 58,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10240 hom., cov: 34)
  • Exomes 𝑓: 0.37 (48185 hom.)
• Consequence: APIP NM_015957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.542

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=-0.83).
• BP6: Variant 11-34916054-A-T is Benign according to our data. Variant chr11-34916054-A-T is described in ClinVar as [Benign]. Clinvar id is 1252351.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/exons	MANE	UniProt
APIP	NM_015957.4	c.57+174T>A		intron_variant		ENST00000395787.4
APIP	XM_011520154.4	c.13+174T>A		intron_variant
PDHX	XM_011520390.2	c.-21+116A>T		intron_variant
APIP	XM_017017875.3	c.-301+174T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APIP	ENST00000395787.4	c.57+174T>A		intron_variant		1	NM_015957.4	P1
PDHX	ENST00000533550.5	c.-21+116A>T		intron_variant		4
APIP	ENST00000527830.1	n.124+174T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54170 AN: 151954 Hom.: 10246 Cov.: 34

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.370 AC: 242961 AN: 656916 Hom.: 48185 Cov.: 9 AF XY: 0.373 AC XY: 125811 AN XY: 336866

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.716

Gnomad4 SAS exome AF: 0.469

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.336

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.356 AC: 54171 AN: 152072 Hom.: 10240 Cov.: 34 AF XY: 0.367 AC XY: 27271 AN XY: 74366

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.341

Alfa AF: 0.350 Hom.: 1206

Bravo AF: 0.349

Asia WGS AF: 0.591 AC: 2057 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 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.8
DANN	Benign	0.53

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: rs2016821; hg19: chr11-34937601;