rs75468446

Variant names:

• chr17-2666133-T-C
• rs75468446
• NM_000430.4:c.192+43T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000430.4(PAFAH1B1):​c.192+43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,344,366 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (164 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (109 hom.)
• Consequence: PAFAH1B1 NM_000430.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.328
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-2666133-T-C is Benign according to our data. Variant chr17-2666133-T-C is described in ClinVar as [Benign]. Clinvar id is 256110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.192+43T>C		intron_variant	Intron 4 of 10	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.192+43T>C		intron_variant	Intron 4 of 10	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3737 AN: 152160 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00627 AC: 921 AN: 146842 AF XY: 0.00485

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00230 AC: 2738 AN: 1192088 Hom.: 109 Cov.: 19 AF XY: 0.00198 AC XY: 1167 AN XY: 590222

African (AFR) AF: 0.0833 AC: 2224 AN: 26710

American (AMR) AF: 0.00517 AC: 145 AN: 28066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22226

East Asian (EAS) AF: 0.00 AC: 0 AN: 33824

South Asian (SAS) AF: 0.0000999 AC: 7 AN: 70098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44138

Middle Eastern (MID) AF: 0.00197 AC: 7 AN: 3546

European-Non Finnish (NFE) AF: 0.0000875 AC: 80 AN: 913818

Other (OTH) AF: 0.00554 AC: 275 AN: 49662

GnomAD4 genome AF: 0.0246 AC: 3750 AN: 152278 Hom.: 164 Cov.: 32 AF XY: 0.0247 AC XY: 1836 AN XY: 74478

African (AFR) AF: 0.0859 AC: 3568 AN: 41532

American (AMR) AF: 0.00785 AC: 120 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0124 Hom.: 19

Bravo AF: 0.0275

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.80
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs75468446; hg19: chr17-2569427;