NM_015957.4:c.19C>T

Variant names:

• chr11-34916266-G-A
• rs2956114
• NM_015957.4:c.19C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 31 publications found

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]

PDHX Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3-binding protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APIP	NM_015957.4	MANE Select	c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	NP_057041.2	Q96GX9-1
	PDHX	NM_001135024.2		c.-241G>A		upstream_gene	N/A	NP_001128496.2	A0A8C8MSB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APIP	ENST00000395787.4	TSL:1 MANE Select	c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	ENSP00000379133.3	Q96GX9-1
	APIP	ENST00000901543.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 8	ENSP00000571602.1
	APIP	ENST00000937716.1		c.19C>T	p.Arg7Trp	missense	Exon 1 of 7	ENSP00000607775.1

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

GnomAD2 exomes AF: 0.406 AC: 97081 AN: 239410 AF XY: 0.407

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 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

African (AFR) AF: 0.259 AC: 8660 AN: 33444

American (AMR) AF: 0.409 AC: 18217 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10844 AN: 26086

East Asian (EAS) AF: 0.725 AC: 28737 AN: 39652

South Asian (SAS) AF: 0.476 AC: 40979 AN: 86090

European-Finnish (FIN) AF: 0.395 AC: 20787 AN: 52598

Middle Eastern (MID) AF: 0.384 AC: 2203 AN: 5738

European-Non Finnish (NFE) AF: 0.341 AC: 379462 AN: 1111186

Other (OTH) AF: 0.376 AC: 22658 AN: 60272

GnomAD4 genome AF: 0.354 AC: 53852 AN: 152258 Hom.: 10156 Cov.: 36 AF XY: 0.364 AC XY: 27126 AN XY: 74446

African (AFR) AF: 0.257 AC: 10664 AN: 41564

American (AMR) AF: 0.405 AC: 6198 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1511 AN: 3468

East Asian (EAS) AF: 0.740 AC: 3827 AN: 5170

South Asian (SAS) AF: 0.487 AC: 2353 AN: 4830

European-Finnish (FIN) AF: 0.410 AC: 4349 AN: 10604

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.351 AC: 23855 AN: 68002

Other (OTH) AF: 0.339 AC: 716 AN: 2112

Alfa AF: 0.355 Hom.: 44383

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pyruvate dehydrogenase E3-binding protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.27
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
PromoterAI		0.021	Neutral
Varity_R		0.054
gMVP		0.52
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2956114; hg19: chr11-34937813; COSMIC: COSV53507442; COSMIC: COSV53507442;