17-39684607-G-C

Variant names:

• chr17-39684607-G-C
• rs35464006
• NM_033419.5:c.422C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033419.5(PGAP3):​c.422C>G​(p.Ala141Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,611,510 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (79 hom.)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.51
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071570873).
• BP6: Variant 17-39684607-G-C is Benign according to our data. Variant chr17-39684607-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00753 (1147/152348) while in subpopulation NFE AF = 0.00942 (641/68028). AF 95% confidence interval is 0.00882. There are 11 homozygotes in GnomAd4. There are 622 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	NM_033419.5	MANE Select	c.422C>G	p.Ala141Gly	missense	Exon 3 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.422C>G	p.Ala141Gly	missense	Exon 3 of 7	NP_001278657.1
	PGAP3	NM_001291730.2		c.422C>G	p.Ala141Gly	missense	Exon 3 of 6	NP_001278659.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.422C>G	p.Ala141Gly	missense	Exon 3 of 8	ENSP00000300658.4
	PGAP3	ENST00000429199.6	TSL:2	c.422C>G	p.Ala141Gly	missense	Exon 3 of 7	ENSP00000415765.2
	PGAP3	ENST00000579146.5	TSL:2	c.422C>G	p.Ala141Gly	missense	Exon 3 of 4	ENSP00000463234.1

Frequencies

GnomAD3 genomes AF: 0.00753 AC: 1146 AN: 152230 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00822 AC: 2041 AN: 248208 AF XY: 0.00813

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00698

GnomAD4 exome AF: 0.00826 AC: 12057 AN: 1459162 Hom.: 79 Cov.: 31 AF XY: 0.00802 AC XY: 5823 AN XY: 725832

African (AFR) AF: 0.00141 AC: 47 AN: 33328

American (AMR) AF: 0.00106 AC: 47 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.00485 AC: 126 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85920

European-Finnish (FIN) AF: 0.0332 AC: 1774 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00874 AC: 9709 AN: 1110860

Other (OTH) AF: 0.00581 AC: 350 AN: 60236

GnomAD4 genome AF: 0.00753 AC: 1147 AN: 152348 Hom.: 11 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74490

African (AFR) AF: 0.00125 AC: 52 AN: 41588

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0354 AC: 376 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00942 AC: 641 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00695 Hom.: 5

Bravo AF: 0.00463

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00839 AC: 1018

EpiCase AF: 0.00791

EpiControl AF: 0.00755

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PGAP3: BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 14, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.49	T
Polyphen		0.31	B
Vest4		0.66
MVP		0.64
MPC		0.46
ClinPred		0.022	T
GERP RS		4.5
PromoterAI		-0.028	Neutral
Varity_R		0.52
gMVP		0.40
Mutation Taster		=70/30	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: rs35464006; hg19: chr17-37840860;