rs797045865

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000430.4(PAFAH1B1):​c.703_704delGA​(p.Glu235fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

PAFAH1B1
NM_000430.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
PAFAH1B1 (HGNC:8574): (platelet activating factor acetylhydrolase 1b regulatory subunit 1) This locus was identified as encoding a gene that when mutated or lost caused the lissencephaly associated with Miller-Dieker lissencephaly syndrome. This gene encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acteylhydrolase, a heterotrimeric enzyme that specifically catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor (identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist: one composed of multiple subunits, the other, a single subunit. In addition, a single-subunit isoform of this enzyme is found in serum. [provided by RefSeq, Apr 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-2674087-CAG-C is Pathogenic according to our data. Variant chr17-2674087-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAFAH1B1NM_000430.4 linkuse as main transcriptc.703_704delGA p.Glu235fs frameshift_variant 8/11 ENST00000397195.10 NP_000421.1 P43034-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAFAH1B1ENST00000397195.10 linkuse as main transcriptc.703_704delGA p.Glu235fs frameshift_variant 8/111 NM_000430.4 ENSP00000380378.4 P43034-1

Frequencies

GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 30, 2016- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 22, 2018The c.703_704delGA pathogenic variant in the PAFAH1B1 gene has been reported previously as a denovo variant in an individual with isolated lissencephaly sequence (ILS) (Pilz et al., 1998). Thedeletion causes a frameshift starting with codon Glutamic acid 235, changes this amino acid to aMethionine residue and creates a premature Stop codon at position 20 of the new reading frame,denoted p.Glu235MetfsX20. This pathogenic variant is predicted to cause loss of normal proteinfunction either through protein truncation or nonsense-mediated mRNA decay. Furthermore, thec.703_704delGA variant is not observed in large population cohorts (Lek et al., 2016). The presence of this pathogenic variant is consistent with the diagnosis of a PAFAH1B1-related disorder in this individual. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
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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.

Other links and lift over

dbSNP: rs797045865; hg19: chr17-2577381; API