17-2593862-C-CCCCGGG

Position:

• chr17-2593862-C-CCCCGGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000430.4(PAFAH1B1):​c.-325_-320dup 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck. 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/exons	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.-325_-320dup		5_prime_UTR_variant	1/11	ENST00000397195.10	NP_000421.1
PAFAH1B1	XM_011523901.3	c.-325_-320dup		5_prime_UTR_variant	1/12		XP_011522203.1
PAFAH1B1	XM_017024701.2	c.-191+542_-191+547dup		intron_variant			XP_016880190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.-325_-320dup		5_prime_UTR_variant	1/11	1	NM_000430.4	ENSP00000380378	P1
PAFAH1B1	ENST00000576586.5	c.-191+542_-191+547dup		intron_variant		4		ENSP00000461087
PAFAH1B1	ENST00000575477.5	n.58_63dup		non_coding_transcript_exon_variant	1/4	5
PAFAH1B1	ENST00000676201.1	n.49+170_49+175dup		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.000353

Gnomad4 AMR AF: 0.000877

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00400

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000921

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly/Subcortical Band Heterotopia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886052706; hg19: chr17-2497156;