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: G2P, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000430.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	NM_000430.4	MANE Select	c.162delA	p.Lys54AsnfsTer15	frameshift	Exon 4 of 11	NP_000421.1	P43034-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	ENST00000397195.10	TSL:1 MANE Select	c.162delA	p.Lys54AsnfsTer15	frameshift	Exon 4 of 11	ENSP00000380378.4	P43034-1
	PAFAH1B1	ENST00000572915.6	TSL:1	n.273-932delA		intron	N/A
	PAFAH1B1	ENST00000674608.1		c.216delA	p.Lys72AsnfsTer15	frameshift	Exon 5 of 12	ENSP00000501976.1	A0A6Q8PFU3

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Lissencephaly due to LIS1 mutation (5)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;