17-2593327-C-T

Position:

• chr17-2593327-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000576586.5(PAFAH1B1):​c.-194C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 152,462 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 32)
  • Exomes 𝑓: 0.030 (0 hom.)
• Consequence: PAFAH1B1 ENST00000576586.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.202

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-2593327-C-T is Benign according to our data. Variant chr17-2593327-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1321740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2544/152198) while in subpopulation NFE AF= 0.0259 (1759/68000). AF 95% confidence interval is 0.0249. There are 33 homozygotes in gnomad4. There are 1193 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2544 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAFAH1B1	XM_017024701.2	c.-194C>T		5_prime_UTR_variant	1/11		XP_016880190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000576586.5	c.-194C>T		5_prime_UTR_variant	1/5	4		ENSP00000461087

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2543 AN: 152080 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0173

GnomAD4 exome AF: 0.0303 AC: 8 AN: 264 Hom.: 0 Cov.: 0 AF XY: 0.0297 AC XY: 6 AN XY: 202

Gnomad4 AFR 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: 0.0330

Gnomad4 OTH exome AF: 0.0455

GnomAD4 genome AF: 0.0167 AC: 2544 AN: 152198 Hom.: 33 Cov.: 32 AF XY: 0.0160 AC XY: 1193 AN XY: 74406

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0120 Hom.: 7

Bravo AF: 0.0153

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.8
DANN	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62068214; hg19: chr17-2496621;