chr11-34916379-C-G

Position:

chr11-34916379-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.789

Variant links:

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]

APIP links:

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 links:

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ACMG classification

Classification made for transcript

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	Effect	#exon/exons	MANE	Protein
APIP	NM_015957.4 linkuse as main transcript	c.-95G>C	5_prime_UTR_variant	1/7	ENST00000395787.4	NP_057041.2
APIP	XM_011520154.4 linkuse as main transcript	c.-139G>C	5_prime_UTR_variant	1/8		XP_011518456.1
APIP	XM_017017875.3 linkuse as main transcript	c.-452G>C	5_prime_UTR_variant	1/8		XP_016873364.1
PDHX	XM_011520390.2 linkuse as main transcript	c.-21+441C>G	intron_variant			XP_011518692.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APIP	ENST00000395787.4 linkuse as main transcript	c.-95G>C	5_prime_UTR_variant	1/7	1	NM_015957.4	ENSP00000379133	P1	Q96GX9-1
PDHX	ENST00000448838.8 linkuse as main transcript	c.-128C>G	5_prime_UTR_variant	1/11	5		ENSP00000389404
PDHX	ENST00000533550.5 linkuse as main transcript	c.-21+441C>G	intron_variant		4		ENSP00000431281
APIP	ENST00000527830.1 linkuse as main transcript		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000860

AC:

131

AN:

152256

Hom.:

Cov.:

show subpopulations

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:

AN:

151906

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

82844

show subpopulations

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.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

694042

show subpopulations

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.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74520

show subpopulations

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.:

Bravo

AF:

0.000918

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 16, 2021

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

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.18

MutationTaster

Benign

0.77

D;A

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over