rs77153143

chr17-2674050-A-Cchr17-2674050-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000430.4(PAFAH1B1):c.672-10A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,582,740 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (56 hom.)
• Consequence: PAFAH1B1 NM_000430.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005175
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.12

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=-0.68).
• BP6: Variant 17-2674050-A-C is Benign according to our data. Variant chr17-2674050-A-C is described in ClinVar as [Benign]. Clinvar id is 92999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-2674050-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAFAH1B1	NM_000430.4	c.672-10A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397195.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.672-10A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000430.4	P1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2472 AN: 152170 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00438 AC: 1100 AN: 251348 Hom.: 22 AF XY: 0.00315 AC XY: 428 AN XY: 135858

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00187 AC: 2681 AN: 1430452 Hom.: 56 Cov.: 26 AF XY: 0.00162 AC XY: 1159 AN XY: 713928

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000369

Gnomad4 OTH exome AF: 0.00491

GnomAD4 genome AF: 0.0163 AC: 2476 AN: 152288 Hom.: 65 Cov.: 33 AF XY: 0.0156 AC XY: 1162 AN XY: 74476

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.00903

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0120 Hom.: 15

Bravo AF: 0.0190

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0052
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77153143; hg19: chr17-2577344;