17-2638291-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000430.4(PAFAH1B1):​c.3G>A​(p.Met1?) variant causes a start lost change. 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAFAH1B1
NM_000430.4 start_lost

Scores

6
7
3

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.18
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000430.4 (PAFAH1B1) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-2638291-G-A is Pathogenic according to our data. Variant chr17-2638291-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 159520.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAFAH1B1NM_000430.4 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/11 ENST00000397195.10 NP_000421.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAFAH1B1ENST00000397195.10 linkuse as main transcriptc.3G>A p.Met1? start_lost 2/111 NM_000430.4 ENSP00000380378 P1P43034-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lissencephaly due to LIS1 mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
T;T
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Benign
-0.43
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Uncertain
-2.8
.;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0050
.;D
Sift4G
Uncertain
0.015
D;D
Polyphen
1.0
.;D
Vest4
0.95
MutPred
0.89
Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);
MVP
0.98
ClinPred
0.98
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.55
gMVP
0.43

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587784265; hg19: chr17-2541585; API