NM_000430.4:c.-440_-438delAAG

Variant names:

• chr17-2593754-GAGA-G
• rs886052705
• NM_000430.4:c.-440_-438delAAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000430.4(PAFAH1B1):​c.-440_-438delAAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAFAH1B1 NM_000430.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.-440_-438delAAG		5_prime_UTR_variant	Exon 1 of 11	ENST00000397195.10	NP_000421.1
PAFAH1B1	XM_011523901.3	c.-440_-438delAAG		5_prime_UTR_variant	Exon 1 of 12		XP_011522203.1
PAFAH1B1	XM_017024701.2	c.-191+427_-191+429delAAG		intron_variant	Intron 1 of 10		XP_016880190.1
PAFAH1B1	XM_011523902.4	c.-1035_-1033delAGA		upstream_gene_variant			XP_011522204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.-440_-438delAAG		5_prime_UTR_variant	Exon 1 of 11	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151734 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000431 AC: 1 AN: 232016 Hom.: 0 AF XY: 0.00000845 AC XY: 1 AN XY: 118320

African (AFR) AF: 0.00 AC: 0 AN: 6678

American (AMR) AF: 0.00 AC: 0 AN: 6916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8640

East Asian (EAS) AF: 0.0000454 AC: 1 AN: 22034

South Asian (SAS) AF: 0.00 AC: 0 AN: 2860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 148926

Other (OTH) AF: 0.00 AC: 0 AN: 15258

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151734 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74102

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

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly/Subcortical Band Heterotopia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

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

Other links and lift over

dbSNP: rs886052705; hg19: chr17-2497048;