NM_015957.4:c.-95G>C

Variant names:

• chr11-34916379-C-G
• rs538595954
• NM_015957.4:c.-95G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015957.4(APIP):​c.-95G>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 0.000156 in 1,557,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000080 (1 hom.)
• Consequence: APIP NM_015957.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.659702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APIP	NM_015957.4	c.-95G>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000395787.4	NP_057041.2
PDHX	NM_003477.3	c.-277C>G		upstream_gene_variant		ENST00000227868.9	NP_003468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4	c.-95G>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_015957.4	ENSP00000379133.3
PDHX	ENST00000227868.9	c.-277C>G		upstream_gene_variant		1	NM_003477.3	ENSP00000227868.4

Frequencies

GnomAD3 genomes AF: 0.000860 AC: 131 AN: 152256 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000138 AC: 21 AN: 151906 Hom.: 0 AF XY: 0.000145 AC XY: 12 AN XY: 82844

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.0000797 AC: 112 AN: 1405584 Hom.: 1 Cov.: 46 AF XY: 0.0000663 AC XY: 46 AN XY: 694042

Gnomad4 AFR exome AF: 0.00298

Gnomad4 AMR exome AF: 0.0000812

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152374 Hom.: 0 Cov.: 36 AF XY: 0.000953 AC XY: 71 AN XY: 74520

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000905 Hom.: 0

Bravo AF: 0.000918

ExAC AF: 0.000108 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PDHX c.-277C>G is located in the untranslated mRNA region upstream of the initiation codon. This variant is also located in 5'UTR of APIP gene (c.-95G>C). The variant allele was found at a frequency of 0.00014 in 151906 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PDHX causing Pyruvate Dehydrogenase E3-Binding Protein Deficiency (0.00014 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.-277C>G in individuals affected with Pyruvate Dehydrogenase E3-Binding Protein Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.18	N
Vest4		0.24
GERP RS		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs538595954; hg19: chr11-34937926;