rs113994198

Variant names:

• chr17-2666052-GA-G
• rs113994198
• NM_000430.4:c.162delA

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000430.4(PAFAH1B1):​c.162delA​(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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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:7
• Conservation: PhyloP100: 8.79
• Publications: 5 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 21180.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	c.162delA	p.Lys54AsnfsTer15	frameshift_variant	Exon 4 of 11	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.162delA	p.Lys54AsnfsTer15	frameshift_variant	Exon 4 of 11	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000192 AC: 40 AN: 208810 AF XY: 0.000194

Gnomad AFR exome AF: 0.0000795

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.000188

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.000191

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000320 AC: 1 AN: 31214

American (AMR) AF: 0.000201 AC: 8 AN: 39778

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24104

East Asian (EAS) AF: 0.0000793 AC: 3 AN: 37814

South Asian (SAS) AF: 0.0000626 AC: 5 AN: 79810

European-Finnish (FIN) AF: 0.0000615 AC: 3 AN: 48778

Middle Eastern (MID) AF: 0.000241 AC: 1 AN: 4152

European-Non Finnish (NFE) AF: 0.0000192 AC: 20 AN: 1042414

Other (OTH) AF: 0.0000179 AC: 1 AN: 55894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:5

May 22, 2025

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1, PS2, PM1, PP5; Variant was found in mosaic state (VAF 19%). De novo-status was confirmed via in-house segregation analysis. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

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. -

not provided Pathogenic:2

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9860301, 21410694). ClinVar contains an entry for this variant (Variation ID: 21180). For these reasons, this variant has been classified as Pathogenic. -

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs113994198; hg19: chr17-2569346; COSMIC: COSV68210450; COSMIC: COSV68210450;