Genetic Variant PAFAH1B3:p.Glu56Lys (chr19-42301952-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002573.4(PAFAH1B3):c.166G>A(p.Glu56Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAFAH1B3
NM_002573.4 missense, splice_region

Scores

Splicing: ADA: 0.007946

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.95

Variant links:

Genes affected

PAFAH1B3 (HGNC:8576): (platelet activating factor acetylhydrolase 1b catalytic subunit 3) This gene encodes an acetylhydrolase that catalyzes the removal of an acetyl group from the glycerol backbone of platelet-activating factor. The encoded enzyme is a subunit of the platelet-activating factor acetylhydrolase isoform 1B complex, which consists of the catalytic beta and gamma subunits and the regulatory alpha subunit. This complex functions in brain development. A translocation between this gene on chromosome 19 and the CDC-like kinase 2 gene on chromosome 1 has been observed, and was associated with cognitive disability, ataxia, and atrophy of the brain. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

PAFAH1B3 links:

PRR19 (HGNC:33728): (proline rich 19)

PRR19 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B3	NM_002573.4 link	c.166G>A	p.Glu56Lys	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000262890.8	NP_002564.1	Q15102A0A024R0L6
PRR19	NM_199285.3 link	c.-558C>T		upstream_gene_variant		ENST00000341747.8	NP_954979.2	A6NJB7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B3	ENST00000262890.8 link	c.166G>A	p.Glu56Lys	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_002573.4	ENSP00000262890.2		Q15102
PRR19	ENST00000341747.8 link	c.-558C>T		upstream_gene_variant		5	NM_199285.3	ENSP00000342709.3		A6NJB7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1404452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693458

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166G>A (p.E56K) alteration is located in exon 3 (coding exon 2) of the PAFAH1B3 gene. This alteration results from a G to A substitution at nucleotide position 166, causing the glutamic acid (E) at amino acid position 56 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

.;D;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.50

D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

D;D;.;.;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.012

D;D;.;.;.;.

Sift4G

Benign

0.18

T;T;.;.;.;T

Polyphen

0.99

D;D;.;.;.;.

Vest4

0.30

MutPred

0.53

Gain of methylation at E56 (P = 0.0017);Gain of methylation at E56 (P = 0.0017);Gain of methylation at E56 (P = 0.0017);Gain of methylation at E56 (P = 0.0017);Gain of methylation at E56 (P = 0.0017);Gain of methylation at E56 (P = 0.0017);

MVP

0.69

MPC

0.94

ClinPred

0.98

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.30

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0079

dbscSNV1_RF

Benign

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over