NM_015957.4:c.57+289C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015957.4(APIP):c.57+289C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 525,116 control chromosomes in the GnomAD database, including 7,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3908 hom., cov: 33)

Exomes 𝑓: 0.12 ( 3314 hom. )

Consequence

APIP
NM_015957.4 intron

Scores

Splicing: ADA: 0.00006474

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 11-34915939-G-C is Benign according to our data. Variant chr11-34915939-G-C is described in ClinVar as [Benign]. Clinvar id is 683422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
APIP	NM_015957.4 link	c.57+289C>G	intron_variant	Intron 1 of 6	ENST00000395787.4	NP_057041.2	Q96GX9-1
PDHX	XM_011520390.2 link	c.-21+1G>C	splice_donor_variant, intron_variant	Intron 1 of 10		XP_011518692.1	A0A8C8MSB2
APIP	XM_011520154.4 link	c.13+289C>G	intron_variant	Intron 1 of 7		XP_011518456.1
APIP	XM_017017875.3 link	c.-301+289C>G	intron_variant	Intron 1 of 7		XP_016873364.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
APIP	ENST00000395787.4 link	c.57+289C>G	intron_variant	Intron 1 of 6	1	NM_015957.4	ENSP00000379133.3	Q96GX9-1
PDHX	ENST00000533550.5 link	c.-21+1G>C	splice_donor_variant, intron_variant	Intron 1 of 4	4		ENSP00000431281.1	E9PLU0
APIP	ENST00000527830.1 link	n.124+289C>G	intron_variant	Intron 1 of 5	2
PDHX	ENST00000448838.8 link	c.-568G>C	upstream_gene_variant		5		ENSP00000389404.3	A0A8C8MSB2

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28793

AN:

152094

Hom.:

3901

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0866

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.177

GnomAD4 exome

AF:

0.124

AC:

46102

AN:

372904

Hom.:

3314

Cov.:

AF XY:

0.124

AC XY:

24161

AN XY:

195568

show subpopulations

Gnomad4 AFR exome

AF:

0.389

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.154

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.189

AC:

28834

AN:

152212

Hom.:

3908

Cov.:

AF XY:

0.186

AC XY:

13884

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.391

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.0868

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.176

Alfa

AF:

0.157

Hom.:

340

Bravo

AF:

0.199

Asia WGS

AF:

0.0890

AC:

308

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.1

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000065

dbscSNV1_RF

Benign

0.0

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