rs113994198

Positions:

• chr17-2666052-GA-G
• chr17-2666052-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000430.4(PAFAH1B1):​c.162del​(p.Lys54AsnfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,363,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: PAFAH1B1 NM_000430.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-2666052-GA-G is Pathogenic according to our data. Variant chr17-2666052-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 21180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2666052-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.162del	p.Lys54AsnfsTer15	frameshift_variant	4/11	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.162del	p.Lys54AsnfsTer15	frameshift_variant	4/11	1	NM_000430.4	ENSP00000380378	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000315 AC: 43 AN: 1363958 Hom.: 0 Cov.: 29 AF XY: 0.0000340 AC XY: 23 AN XY: 676078

Gnomad4 AFR exome AF: 0.0000320

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000415

Gnomad4 EAS exome AF: 0.0000793

Gnomad4 SAS exome AF: 0.0000626

Gnomad4 FIN exome AF: 0.0000615

Gnomad4 NFE exome AF: 0.0000192

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Aug 28, 2017	This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the PAFAH1B1 gene, also known as LIS1. The patient is mosaic for this variant, at an unknown level. A paternal sample is unavailable, so inheritance of the variant is unknown, but it is assumed to be de novo. The c.162delA variant has been reported multiple times previously in association with lissencephaly (Sakamoto et al., 1998; de Wit et al., 2011; Dobyns and Das, 2014). Other researchers have identified patients who had subcortical band heterotopia that had somatic mosaicism for variants in the PAFAH1B1 gene (PMIDs: 10441340, 11502906, 14581661); their phenotypes were noted to be less severe than individuals not mosaic for the variants. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021180, PMID:9860301). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2024	Reported previously multiple times in association with lissencephaly (PMID: 9860301, 21410694, 20301752); Frameshift 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; This variant is associated with the following publications: (PMID: 21410694, 20301752, 11502906, 14581661, 10441340, 32005694, 36100855, 32906206, 9860301) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21180). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9860301, 21410694). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys54Asnfs*15) 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

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

LitVar

Other links and lift over

dbSNP: rs113994198; hg19: chr17-2569346;