17-2638310-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000430.4(PAFAH1B1):​c.22C>T​(p.Arg8Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PAFAH1B1
NM_000430.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-2638310-C-T is Pathogenic according to our data. Variant chr17-2638310-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8081.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.22C>T p.Arg8Ter stop_gained 2/11 ENST00000397195.10 NP_000421.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAFAH1B1ENST00000397195.10 linkuse as main transcriptc.22C>T p.Arg8Ter stop_gained 2/111 NM_000430.4 ENSP00000380378 P1P43034-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1460466
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726578
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterDec 06, 2023Criteria applied: PVS1, PM2_SUP, PS4_MOD. This variant was detected in a mosaic state (allele fraction in blood 0.12) -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 31, 2014- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 28, 2003- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 07, 2024Previously reported as a mosaic variant in an individual with subcortical band heterotopia, and in the heterozygous state in individuals with lissencephaly (PMID: 14581661, 29671837, 34979677); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32366993, 15719169, 29671837, 22129557, 33484635, 33911214, 34979677, 14581661) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 02, 2021For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 8081). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 14581661, 29671837). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg8*) 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). -
Lissencephaly Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Subcortical band heterotopia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 28, 2003- -
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 03, 2020The variant c.22C>T, p.(Arg8*) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Likely pathogenic according to ACMG guidelines. Inheritance for this variant was mosaic (12-13% allele frequency).The variant likely explains the NDD in this individual. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.82
D
MutationTaster
Benign
1.0
A;A
Vest4
0.94
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs121434489; hg19: chr17-2541604; API