17-2680225-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000430.4(PAFAH1B1):​c.1064G>T​(p.Ser355Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAFAH1B1
NM_000430.4 missense

Scores

13
5
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.42
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PAFAH1B1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.5284 (above the threshold of 3.09). Trascript score misZ: 3.7057 (above the threshold of 3.09). GenCC associations: The gene is linked to lissencephaly due to LIS1 mutation.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAFAH1B1NM_000430.4 linkc.1064G>T p.Ser355Ile missense_variant Exon 10 of 11 ENST00000397195.10 NP_000421.1 P43034-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAFAH1B1ENST00000397195.10 linkc.1064G>T p.Ser355Ile missense_variant Exon 10 of 11 1 NM_000430.4 ENSP00000380378.4 P43034-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461798
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Pathogenic
3.5
H;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D;.
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.83
P;.
Vest4
0.92
MutPred
0.77
Loss of catalytic residue at S355 (P = 0.0079);.;
MVP
0.93
MPC
2.4
ClinPred
0.98
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.96

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: chr17-2583519; API