rs2016814

Variant names:

• chr11-34916150-T-C
• rs2016814
• NM_015957.4:c.57+78A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-34916150-T-C
• chr11-34916150-T-A
• chr11-34916150-T-G

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.57+78A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 1,543,634 control chromosomes in the GnomAD database, including 487,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47695 hom., cov: 34)
  • Exomes 𝑓: 0.79 (439917 hom.)
• Consequence: APIP NM_015957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.69
• Publications: 11 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 (BayesDel_noAF=-0.84).
• BP6: Variant 11-34916150-T-C is Benign according to our data. Variant chr11-34916150-T-C is described in ClinVar as Benign. ClinVar VariationId is 304443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 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.57+78A>G		intron	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APIP	ENST00000395787.4	TSL:1 MANE Select	c.57+78A>G		intron	N/A	ENSP00000379133.3	Q96GX9-1
	PDHX	ENST00000448838.8	TSL:5	c.-357T>C		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000901543.1		c.57+78A>G		intron	N/A	ENSP00000571602.1

Frequencies

GnomAD3 genomes AF: 0.791 AC: 120209 AN: 152060 Hom.: 47674 Cov.: 34

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.775

GnomAD4 exome AF: 0.794 AC: 1105020 AN: 1391456 Hom.: 439917 Cov.: 29 AF XY: 0.793 AC XY: 545101 AN XY: 687690

African (AFR) AF: 0.802 AC: 25087 AN: 31276

American (AMR) AF: 0.642 AC: 23831 AN: 37108

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 20735 AN: 24874

East Asian (EAS) AF: 0.821 AC: 29550 AN: 35986

South Asian (SAS) AF: 0.746 AC: 59431 AN: 79704

European-Finnish (FIN) AF: 0.770 AC: 33879 AN: 43980

Middle Eastern (MID) AF: 0.794 AC: 3235 AN: 4076

European-Non Finnish (NFE) AF: 0.802 AC: 863368 AN: 1076750

Other (OTH) AF: 0.796 AC: 45904 AN: 57702

GnomAD4 genome AF: 0.790 AC: 120272 AN: 152178 Hom.: 47695 Cov.: 34 AF XY: 0.788 AC XY: 58640 AN XY: 74376

African (AFR) AF: 0.802 AC: 33301 AN: 41520

American (AMR) AF: 0.718 AC: 10990 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2898 AN: 3466

East Asian (EAS) AF: 0.831 AC: 4281 AN: 5152

South Asian (SAS) AF: 0.730 AC: 3525 AN: 4826

European-Finnish (FIN) AF: 0.770 AC: 8162 AN: 10604

Middle Eastern (MID) AF: 0.791 AC: 231 AN: 292

European-Non Finnish (NFE) AF: 0.801 AC: 54471 AN: 67990

Other (OTH) AF: 0.767 AC: 1619 AN: 2110

Alfa AF: 0.749 Hom.: 2495

Bravo AF: 0.788

Asia WGS AF: 0.750 AC: 2606 AN: 3472

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.50
PhyloP100		-1.7
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2016814; hg19: chr11-34937697;