chr17-2666046-CT-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000430.4(PAFAH1B1):c.152delT(p.Leu51TrpfsTer18) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAFAH1B1
NM_000430.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.55

Publications

2 publications found

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]

PAFAH1B1 Gene-Disease associations (from GenCC):

lissencephaly due to LIS1 mutation
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

PAFAH1B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 17-2666046-CT-C is Pathogenic according to our data. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666046-CT-C is described in CliVar as Pathogenic. Clinvar id is 159506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4 link	c.152delT	p.Leu51TrpfsTer18	frameshift_variant	Exon 4 of 11	ENST00000397195.10	NP_000421.1	P43034-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10 link	c.152delT	p.Leu51TrpfsTer18	frameshift_variant	Exon 4 of 11	1	NM_000430.4	ENSP00000380378.4		P43034-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1369018

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678410

African (AFR)

AF:

0.00

AC:

AN:

31440

American (AMR)

AF:

0.00

AC:

AN:

40262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24216

East Asian (EAS)

AF:

0.00

AC:

AN:

37850

South Asian (SAS)

AF:

0.00

AC:

AN:

80246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4194

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045794

Other (OTH)

AF:

0.00

AC:

AN:

56192

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lissencephaly due to LIS1 mutation

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 159506). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PAFAH1B1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu51Trpfs*18) in the PAFAH1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAFAH1B1 are known to be pathogenic (PMID: 1671808, 11115846, 14581661). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over