17-2670247-G-A

Position:

• chr17-2670247-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000397195.10(PAFAH1B1):​c.484G>A​(p.Gly162Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAFAH1B1 ENST00000397195.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000397195.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-2670248-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803050.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAFAH1B1. . Gene score misZ 3.5284 (greater than the threshold 3.09). Trascript score misZ 3.7057 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly due to LIS1 mutation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 17-2670247-G-A is Pathogenic according to our data. Variant chr17-2670247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.484G>A	p.Gly162Ser	missense_variant	6/11	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.484G>A	p.Gly162Ser	missense_variant	6/11	1	NM_000430.4	ENSP00000380378	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2001	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Dec 19, 2014	Our laboratory reported dual molecular diagnoses in PAFAH1B1 (NM_000430.3, c.484G>A) and FGD1 (NM_004463.2, c.527delC) in this individual with reported features of intrauterine growth restriction, delayed motor milestones, delayed speech, autism, intellectual disability, hearing loss, hypotonia, seizure disorder, ataxia, dysmorphic features, short stature, microcephaly, failure to thrive, eye anomalies, skeletal abnormalities and scoliosis, and structural brain anomalies. The PAFAH1B1 variant has been reported in one patient with a mild LIS1 phenotype [PMID: 11115846, 12885786]. The FGD1 variant is predicted to cause a frameshift and is categorized as deleterious by ACMGG guidelines [PMID: 18414213]. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 162 of the PAFAH1B1 protein (p.Gly162Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lissencephaly (PMID: 1115846, 25140959). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8079). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAFAH1B1 function (PMID: 12885786). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.026	D
Sift4G	Benign	0.088	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Gain of disorder (P = 0.0458);
MVP		0.94
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.72

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: rs121434487; hg19: chr17-2573541;