NM_033419.5:c.919C>G

Variant names:

• chr17-39672847-G-C
• rs769690688
• NM_033419.5:c.919C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033419.5(PGAP3):​c.919C>G​(p.Leu307Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L307L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24421751).

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.919C>G	p.Leu307Val	missense	Exon 8 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.856C>G	p.Leu286Val	missense	Exon 7 of 7	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.766C>G	p.Leu256Val	missense	Exon 7 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.919C>G	p.Leu307Val	missense	Exon 8 of 8	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.856C>G	p.Leu286Val	missense	Exon 7 of 7	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.766C>G	p.Leu256Val	missense	Exon 7 of 7	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250512 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.085
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.50
Sift	Benign	0.076	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.18
MutPred		0.47		Loss of helix (P = 0.0558)
MVP		0.47
MPC		1.1
ClinPred		0.80	D
GERP RS		2.1
Varity_R		0.44
gMVP		0.33
Mutation Taster		=42/58	disease causing

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: rs769690688; hg19: chr17-37829100;