17-39684607-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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:3
• Conservation: PhyloP100: 8.51

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Post-GPI attachment to proteins factor 3 (size 299) in uniprot entity PGAP3_HUMAN there are 30 pathogenic changes around while only 12 benign (71%) in NM_033419.5
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP3	NM_033419.5	c.422C>G	p.Ala141Gly	missense_variant	3/8	ENST00000300658.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP3	ENST00000300658.9	c.422C>G	p.Ala141Gly	missense_variant	3/8	1	NM_033419.5	P1

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

GnomAD3 exomes AF: 0.00822 AC: 2041 AN: 248208 Hom.: 21 AF XY: 0.00813 AC XY: 1091 AN XY: 134234

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 SAS 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

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00485

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.0332

Gnomad4 NFE exome AF: 0.00874

Gnomad4 OTH exome AF: 0.00581

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

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0354

Gnomad4 NFE AF: 0.00942

Gnomad4 OTH AF: 0.00520

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PGAP3: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 14, 2015	- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.49	T;T;T;.
Polyphen		0.31	.;B;.;.
Vest4		0.66
MVP		0.64
MPC		0.46
ClinPred		0.022	T
GERP RS		4.5
Varity_R		0.52
gMVP		0.40

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: rs35464006; hg19: chr17-37840860;