rs121434490

Positions:

• chr17-2674218-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000430.4(PAFAH1B1):​c.830A>C​(p.His277Pro) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAFAH1B1 NM_000430.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.942
• PP5: Variant 17-2674218-A-C is Pathogenic according to our data. Variant chr17-2674218-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8082.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.830A>C	p.His277Pro	missense_variant	8/11	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.830A>C	p.His277Pro	missense_variant	8/11	1	NM_000430.4	ENSP00000380378	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 09, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.8	D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.81		Gain of disorder (P = 0.0681);.;
MVP		0.93
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.98

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: rs121434490; hg19: chr17-2577512;