rs116237011

chr17-2670237-C-Gchr17-2670237-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000430.4(PAFAH1B1):c.474C>G(p.Phe158Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F158F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAFAH1B1 NM_000430.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a repeat WD 2 (size 39) in uniprot entity LIS1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000430.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PAFAH1B1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAFAH1B1	NM_000430.4	c.474C>G	p.Phe158Leu	missense_variant	6/11	ENST00000397195.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.474C>G	p.Phe158Leu	missense_variant	6/11	1	NM_000430.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.73		Loss of catalytic residue at F158 (P = 0.0398);
MVP		0.91
MPC		2.1
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.62
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs116237011; hg19: chr17-2573531;