chr17-2593862-C-CCCCGGG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 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.
• BS2: High AC in GnomAd4 at 51 AD gene.

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.-325_-320dupGGGCCC		5_prime_UTR	Exon 1 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.-325_-320dupGGGCCC		5_prime_UTR	Exon 1 of 11	ENSP00000380378.4	P43034-1
	PAFAH1B1	ENST00000863847.1		c.-453_-448dupGGGCCC		5_prime_UTR	Exon 1 of 12	ENSP00000533906.1
	PAFAH1B1	ENST00000863848.1		c.-459_-454dupGGGCCC		5_prime_UTR	Exon 1 of 12	ENSP00000533907.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lissencephaly/Subcortical Band Heterotopia (1)

Computational scores

Source: dbNSFP v4.9

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;