rs2956113

Variant names:

• chr11-34916337-G-A
• rs2956113
• NM_015957.4:c.-53C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-34916337-G-A
• chr11-34916337-G-C
• chr11-34916337-G-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.-53C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,599,314 control chromosomes in the GnomAD database, including 110,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10153 hom., cov: 36)
  • Exomes 𝑓: 0.36 (100591 hom.)
• Consequence: APIP NM_015957.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08
• Publications: 13 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=-0.76).
• BP6: Variant 11-34916337-G-A is Benign according to our data. Variant chr11-34916337-G-A is described in ClinVar as Benign. ClinVar VariationId is 304449.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.-53C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_057041.2	Q96GX9-1
	APIP	NM_015957.4	MANE Select	c.-53C>T		5_prime_UTR	Exon 1 of 7	NP_057041.2	Q96GX9-1
	PDHX	NM_001135024.2		c.-170G>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.-53C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000379133.3	Q96GX9-1
	APIP	ENST00000395787.4	TSL:1 MANE Select	c.-53C>T		5_prime_UTR	Exon 1 of 7	ENSP00000379133.3	Q96GX9-1
	APIP	ENST00000901543.1		c.-53C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000571602.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53857 AN: 152156 Hom.: 10163 Cov.: 36

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.435

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: 0.342

GnomAD2 exomes AF: 0.413 AC: 87642 AN: 212210 AF XY: 0.414

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.365 AC: 527647 AN: 1447042 Hom.: 100591 Cov.: 48 AF XY: 0.368 AC XY: 264145 AN XY: 718580

African (AFR) AF: 0.259 AC: 8592 AN: 33126

American (AMR) AF: 0.410 AC: 17571 AN: 42854

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10744 AN: 25836

East Asian (EAS) AF: 0.725 AC: 28266 AN: 39008

South Asian (SAS) AF: 0.476 AC: 40227 AN: 84464

European-Finnish (FIN) AF: 0.395 AC: 20251 AN: 51226

Middle Eastern (MID) AF: 0.384 AC: 2198 AN: 5730

European-Non Finnish (NFE) AF: 0.341 AC: 377347 AN: 1105084

Other (OTH) AF: 0.376 AC: 22451 AN: 59714

GnomAD4 genome AF: 0.354 AC: 53844 AN: 152272 Hom.: 10153 Cov.: 36 AF XY: 0.364 AC XY: 27121 AN XY: 74456

African (AFR) AF: 0.256 AC: 10660 AN: 41566

American (AMR) AF: 0.405 AC: 6196 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1510 AN: 3468

East Asian (EAS) AF: 0.741 AC: 3828 AN: 5166

South Asian (SAS) AF: 0.487 AC: 2352 AN: 4832

European-Finnish (FIN) AF: 0.410 AC: 4350 AN: 10610

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

European-Non Finnish (NFE) AF: 0.351 AC: 23852 AN: 68002

Other (OTH) AF: 0.339 AC: 717 AN: 2116

Alfa AF: 0.283 Hom.: 1183

Bravo AF: 0.346

Asia WGS AF: 0.589 AC: 2051 AN: 3476

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	-0.76
CADD	Benign	4.7
DANN	Benign	0.89
PhyloP100		-1.1
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=78/222	disease causing

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: rs2956113; hg19: chr11-34937884;