NM_033419.5:c.842T>C

Variant names:

• chr17-39673108-A-G
• rs869312817
• NM_033419.5:c.842T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_033419.5(PGAP3):​c.842T>C​(p.Leu281Pro) variant causes a missense 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.07
• Publications: 2 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: Likely_pathogenic. The variant received 7 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, 3 uncertain in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 17-39673108-A-G is Pathogenic according to our data. Variant chr17-39673108-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 224648.Status of the report is no_assertion_criteria_provided, 0 stars.

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.842T>C	p.Leu281Pro	missense	Exon 7 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.779T>C	p.Leu260Pro	missense	Exon 6 of 7	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.689T>C	p.Leu230Pro	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.842T>C	p.Leu281Pro	missense	Exon 7 of 8	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.779T>C	p.Leu260Pro	missense	Exon 6 of 7	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.689T>C	p.Leu230Pro	missense	Exon 6 of 7	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456668 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724038

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110082

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperphosphatasia with intellectual disability syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.62		Loss of helix (P = 0.0196)
MVP		0.55
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs869312817; hg19: chr17-37829361;