rs2956112

Variant names:

• chr11-34916354-A-G
• rs2956112
• NM_015957.4:c.-70T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-34916354-A-G
• chr11-34916354-A-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.-70T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 1,585,520 control chromosomes in the GnomAD database, including 498,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46804 hom., cov: 36)
  • Exomes 𝑓: 0.79 (451838 hom.)
• Consequence: APIP NM_015957.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.83
• Publications: 15 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=-0.9).
• BP6: Variant 11-34916354-A-G is Benign according to our data. Variant chr11-34916354-A-G is described in ClinVar as Benign. ClinVar VariationId is 304450.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.-70T>C		5_prime_UTR	Exon 1 of 7	NP_057041.2	Q96GX9-1
	PDHX	NM_001135024.2		c.-153A>G		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.-70T>C		5_prime_UTR	Exon 1 of 7	ENSP00000379133.3	Q96GX9-1
	PDHX	ENST00000448838.8	TSL:5	c.-153A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2
	PDHX	ENST00000448838.8	TSL:5	c.-153A>G		5_prime_UTR	Exon 1 of 11	ENSP00000389404.3	A0A8C8MSB2

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119126 AN: 152154 Hom.: 46789 Cov.: 36

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.717

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.768 AC: 147964 AN: 192750 AF XY: 0.773

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.832

Gnomad EAS exome AF: 0.849

Gnomad FIN exome AF: 0.774

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.771

GnomAD4 exome AF: 0.793 AC: 1136521 AN: 1433250 Hom.: 451838 Cov.: 49 AF XY: 0.792 AC XY: 562554 AN XY: 710446

African (AFR) AF: 0.774 AC: 25317 AN: 32712

American (AMR) AF: 0.637 AC: 25940 AN: 40740

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 21354 AN: 25608

East Asian (EAS) AF: 0.823 AC: 31340 AN: 38094

South Asian (SAS) AF: 0.745 AC: 61833 AN: 82962

European-Finnish (FIN) AF: 0.772 AC: 38729 AN: 50152

Middle Eastern (MID) AF: 0.803 AC: 4575 AN: 5696

European-Non Finnish (NFE) AF: 0.802 AC: 880456 AN: 1098084

Other (OTH) AF: 0.794 AC: 46977 AN: 59202

GnomAD4 genome AF: 0.783 AC: 119181 AN: 152270 Hom.: 46804 Cov.: 36 AF XY: 0.781 AC XY: 58145 AN XY: 74442

African (AFR) AF: 0.775 AC: 32234 AN: 41570

American (AMR) AF: 0.716 AC: 10958 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2901 AN: 3472

East Asian (EAS) AF: 0.831 AC: 4296 AN: 5170

South Asian (SAS) AF: 0.730 AC: 3523 AN: 4828

European-Finnish (FIN) AF: 0.769 AC: 8159 AN: 10606

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

European-Non Finnish (NFE) AF: 0.801 AC: 54467 AN: 67996

Other (OTH) AF: 0.765 AC: 1618 AN: 2114

Alfa AF: 0.797 Hom.: 13020

Bravo AF: 0.779

Asia WGS AF: 0.744 AC: 2588 AN: 3476

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	-0.90
CADD	Benign	1.8
DANN	Benign	0.34
PhyloP100		-3.8
PromoterAI		-0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=296/4	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: rs2956112; hg19: chr11-34937901;