17-39673094-T-A

Variant names:

• chr17-39673094-T-A
• rs760923040
• NM_033419.5:c.856A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_033419.5(PGAP3):​c.856A>T​(p.Ile286Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779

Genes affected

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 19) in uniprot entity PGAP3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP3	NM_033419.5	c.856A>T	p.Ile286Phe	missense_variant	Exon 7 of 8	ENST00000300658.9	NP_219487.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9	c.856A>T	p.Ile286Phe	missense_variant	Exon 7 of 8	1	NM_033419.5	ENSP00000300658.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.71
MutPred		0.61		Loss of helix (P = 0.2271);.;.;
MVP		0.67
MPC		1.1
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.35
gMVP		0.86

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: rs760923040; hg19: chr17-37829347;