Genetic Variant NM_015957.4:c.57+57C>T (chr11-34916171-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015957.4(APIP):c.57+57C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,572,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 36)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

APIP
NM_015957.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.727

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_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
APIP	NM_015957.4 link	c.57+57C>T	intron_variant	Intron 1 of 6	ENST00000395787.4	NP_057041.2	Q96GX9-1
PDHX	XM_011520390.2 link	c.-21+233G>A	intron_variant	Intron 1 of 10		XP_011518692.1	A0A8C8MSB2
APIP	XM_011520154.4 link	c.13+57C>T	intron_variant	Intron 1 of 7		XP_011518456.1
APIP	XM_017017875.3 link	c.-301+57C>T	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+57C>T	intron_variant	Intron 1 of 6	1	NM_015957.4	ENSP00000379133.3	Q96GX9-1
PDHX	ENST00000448838 link	c.-336G>A	5_prime_UTR_variant	Exon 1 of 11	5		ENSP00000389404.3	A0A8C8MSB2
PDHX	ENST00000533550.5 link	c.-21+233G>A	intron_variant	Intron 1 of 4	4		ENSP00000431281.1	E9PLU0
APIP	ENST00000527830.1 link	n.124+57C>T	intron_variant	Intron 1 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000422

AC:

AN:

1420466

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

703744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000457

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.2

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over