11-34916054-A-T

Variant names:

• chr11-34916054-A-T
• rs2016821
• NM_015957.4:c.57+174T>A

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+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
• 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, 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=-0.83).
• BP6: Variant 11-34916054-A-T is Benign according to our data. Variant chr11-34916054-A-T is described in ClinVar as Benign. ClinVar VariationId 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.

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+174T>A		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+174T>A		intron	N/A	ENSP00000379133.3	Q96GX9-1
	APIP	ENST00000901543.1		c.57+174T>A		intron	N/A	ENSP00000571602.1
	APIP	ENST00000937716.1		c.57+174T>A		intron	N/A	ENSP00000607775.1

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

African (AFR) AF: 0.258 AC: 3697 AN: 14336

American (AMR) AF: 0.403 AC: 7664 AN: 19018

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 5862 AN: 14332

East Asian (EAS) AF: 0.716 AC: 21503 AN: 30038

South Asian (SAS) AF: 0.469 AC: 23246 AN: 49558

European-Finnish (FIN) AF: 0.391 AC: 11691 AN: 29890

Middle Eastern (MID) AF: 0.357 AC: 853 AN: 2388

European-Non Finnish (NFE) AF: 0.336 AC: 156144 AN: 464524

Other (OTH) AF: 0.375 AC: 12301 AN: 32832

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

African (AFR) AF: 0.265 AC: 10994 AN: 41466

American (AMR) AF: 0.406 AC: 6210 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3470

East Asian (EAS) AF: 0.741 AC: 3817 AN: 5152

South Asian (SAS) AF: 0.487 AC: 2352 AN: 4828

European-Finnish (FIN) AF: 0.411 AC: 4346 AN: 10584

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23840 AN: 67966

Other (OTH) AF: 0.341 AC: 721 AN: 2112

Alfa AF: 0.350 Hom.: 1206

Bravo AF: 0.349

Asia WGS AF: 0.591 AC: 2057 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.8
DANN	Benign	0.53
PhyloP100		-0.54
PromoterAI		0.0078	Neutral
Mutation Taster		=100/0	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: rs2016821; hg19: chr11-34937601;