11-34916151-G-A

Variant names:

• chr11-34916151-G-A
• rs16926448
• NM_015957.4:c.57+77C>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.57+77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,545,654 control chromosomes in the GnomAD database, including 15,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3904 hom., cov: 35)
  • Exomes 𝑓: 0.12 (11479 hom.)
• Consequence: APIP NM_015957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0120
• Publications: 7 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, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-34916151-G-A is Benign according to our data. Variant chr11-34916151-G-A is described in ClinVar as Benign. ClinVar VariationId is 304444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 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+77C>T		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+77C>T		intron	N/A	ENSP00000379133.3	Q96GX9-1
	PDHX	ENST00000448838.8	TSL:5	c.-356G>A		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	APIP	ENST00000901543.1		c.57+77C>T		intron	N/A	ENSP00000571602.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28777 AN: 152050 Hom.: 3897 Cov.: 35

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.119 AC: 165695 AN: 1393486 Hom.: 11479 Cov.: 33 AF XY: 0.119 AC XY: 81852 AN XY: 688866

African (AFR) AF: 0.397 AC: 12456 AN: 31338

American (AMR) AF: 0.0845 AC: 3170 AN: 37514

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3737 AN: 24932

East Asian (EAS) AF: 0.0972 AC: 3507 AN: 36082

South Asian (SAS) AF: 0.119 AC: 9495 AN: 79980

European-Finnish (FIN) AF: 0.116 AC: 5137 AN: 44302

Middle Eastern (MID) AF: 0.152 AC: 621 AN: 4086

European-Non Finnish (NFE) AF: 0.111 AC: 120048 AN: 1077534

Other (OTH) AF: 0.130 AC: 7524 AN: 57718

GnomAD4 genome AF: 0.189 AC: 28818 AN: 152168 Hom.: 3904 Cov.: 35 AF XY: 0.186 AC XY: 13870 AN XY: 74408

African (AFR) AF: 0.390 AC: 16205 AN: 41506

American (AMR) AF: 0.110 AC: 1684 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3470

East Asian (EAS) AF: 0.0869 AC: 448 AN: 5158

South Asian (SAS) AF: 0.114 AC: 551 AN: 4832

European-Finnish (FIN) AF: 0.117 AC: 1240 AN: 10604

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7732 AN: 67974

Other (OTH) AF: 0.176 AC: 372 AN: 2114

Alfa AF: 0.0850 Hom.: 159

Bravo AF: 0.199

Asia WGS AF: 0.0900 AC: 311 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.78
CADD	Benign	7.8
DANN	Benign	0.88
PhyloP100		-0.012
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16926448; hg19: chr11-34937698;