NM_033419.5:c.856A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I286V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779
• Publications: 1 publications found

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]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	NM_033419.5	MANE Select	c.856A>T	p.Ile286Phe	missense	Exon 7 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.793A>T	p.Ile265Phe	missense	Exon 6 of 7	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.703A>T	p.Ile235Phe	missense	Exon 6 of 7	NP_001278655.1	Q96FM1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.856A>T	p.Ile286Phe	missense	Exon 7 of 8	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.793A>T	p.Ile265Phe	missense	Exon 6 of 7	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.703A>T	p.Ile235Phe	missense	Exon 6 of 7	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.78
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	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
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs760923040; hg19: chr17-37829347;