11-34916266-G-A

Position:

• chr11-34916266-G-A

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.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,611,870 control chromosomes in the GnomAD database, including 111,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10156 hom., cov: 36)
  • Exomes 𝑓: 0.36 (101724 hom.)
• Consequence: APIP NM_015957.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.267

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 (MetaRNN=2.184286E-6).
• BP6: Variant 11-34916266-G-A is Benign according to our data. Variant chr11-34916266-G-A is described in ClinVar as [Benign]. Clinvar id is 304445.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	Protein	UniProt
APIP	NM_015957.4	c.19C>T	p.Arg7Trp	missense_variant	1/7	ENST00000395787.4	NP_057041.2
APIP	XM_011520154.4	c.-26C>T		5_prime_UTR_variant	1/8		XP_011518456.1
APIP	XM_017017875.3	c.-339C>T		5_prime_UTR_variant	1/8		XP_016873364.1
PDHX	XM_011520390.2	c.-21+328G>A		intron_variant			XP_011518692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4	c.19C>T	p.Arg7Trp	missense_variant	1/7	1	NM_015957.4	ENSP00000379133	P1
PDHX	ENST00000448838.8	c.-241G>A		5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5	c.-21+328G>A		intron_variant		4		ENSP00000431281
APIP	ENST00000527830.1	n.86C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53862 AN: 152144 Hom.: 10165 Cov.: 36

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.436

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: 0.343

GnomAD3 exomes AF: 0.406 AC: 97081 AN: 239410 Hom.: 21321 AF XY: 0.407 AC XY: 53343 AN XY: 131026

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.751

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.349

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.365 AC: 532547 AN: 1459612 Hom.: 101724 Cov.: 75 AF XY: 0.368 AC XY: 267060 AN XY: 726028

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.409

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: 53852 AN: 152258 Hom.: 10156 Cov.: 36 AF XY: 0.364 AC XY: 27126 AN XY: 74446

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.740

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.339

Alfa AF: 0.359 Hom.: 25117

Bravo AF: 0.346

TwinsUK AF: 0.341 AC: 1263

ALSPAC AF: 0.336 AC: 1295

ESP6500AA AF: 0.243 AC: 1067

ESP6500EA AF: 0.355 AC: 3045

ExAC AF: 0.393 AC: 47353

Asia WGS AF: 0.589 AC: 2048 AN: 3474

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	Jun 23, 2018	- -

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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.10
Sift	Benign	0.035	D
Sift4G	Uncertain	0.017	D
Polyphen		0.74	P
Vest4		0.059
MPC		0.33
ClinPred		0.029	T
GERP RS		2.5
Varity_R		0.054
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2956114; hg19: chr11-34937813; COSMIC: COSV53507442; COSMIC: COSV53507442;