chr17-2593862-C-CCCCGGG

Variant names:

• chr17-2593862-C-CCCCGGG
• rs886052706
• NM_000430.4:c.-325_-320dupGGGCCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000430.4(PAFAH1B1):​c.-325_-320dupGGGCCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 145,526 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 25)
  • Exomes 𝑓: 0.0 (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: 1.93
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00035 (51/145526) while in subpopulation SAS AF = 0.004 (18/4502). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.-325_-320dupGGGCCC		5_prime_UTR_variant	Exon 1 of 11	ENST00000397195.10	NP_000421.1
PAFAH1B1	XM_011523901.3	c.-325_-320dupGGGCCC		5_prime_UTR_variant	Exon 1 of 12		XP_011522203.1
PAFAH1B1	XM_017024701.2	c.-191+542_-191+547dupGGGCCC		intron_variant	Intron 1 of 10		XP_016880190.1
PAFAH1B1	XM_011523902.4	c.-928_-927insCCCGGG		upstream_gene_variant			XP_011522204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.-325_-320dupGGGCCC		5_prime_UTR_variant	Exon 1 of 11	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes AF: 0.000351 AC: 51 AN: 145420 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000878

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00399

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000921

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 133552 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67602

African (AFR) AF: 0.00 AC: 0 AN: 3534

American (AMR) AF: 0.00 AC: 0 AN: 4200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4980

East Asian (EAS) AF: 0.00 AC: 0 AN: 12724

South Asian (SAS) AF: 0.00 AC: 0 AN: 1824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 85780

Other (OTH) AF: 0.00 AC: 0 AN: 8704

GnomAD4 genome AF: 0.000350 AC: 51 AN: 145526 Hom.: 1 Cov.: 25 AF XY: 0.000366 AC XY: 26 AN XY: 71126

African (AFR) AF: 0.000353 AC: 14 AN: 39648

American (AMR) AF: 0.000877 AC: 13 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4832

South Asian (SAS) AF: 0.00400 AC: 18 AN: 4502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000921 AC: 6 AN: 65154

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 0

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=295/5	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886052706; hg19: chr17-2497156;