17-2674229-T-G

Position:

• chr17-2674229-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000430.4(PAFAH1B1):​c.841T>G​(p.Cys281Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C281R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAFAH1B1 NM_000430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 9 ACMG points.

• PM1: In a repeat WD 5 (size 59) in uniprot entity LIS1_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000430.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-2674229-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 159546.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, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAFAH1B1	NM_000430.4	c.841T>G	p.Cys281Gly	missense_variant	8/11	ENST00000397195.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.841T>G	p.Cys281Gly	missense_variant	8/11	1	NM_000430.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 10, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PAFAH1B1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with glycine at codon 281 of the PAFAH1B1 protein (p.Cys281Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.87	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.5	D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.098	T;T
Polyphen		0.94	P;.
Vest4		0.88
MutPred		0.66		Gain of disorder (P = 0.0183);.;
MVP		0.93
MPC		2.3
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-2577523;