17-39672876-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033419.5(PGAP3):c.900-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,612,766 control chromosomes in the GnomAD database, including 383,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31637 hom., cov: 33)
  • Exomes 𝑓: 0.69 (351587 hom.)
• Consequence: PGAP3 NM_033419.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002155
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.73

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-39672876-A-G is Benign according to our data. Variant chr17-39672876-A-G is described in ClinVar as [Benign]. Clinvar id is 1268616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP3	NM_033419.5	c.900-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000300658.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP3	ENST00000300658.9	c.900-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033419.5	P1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97147 AN: 151920 Hom.: 31609 Cov.: 33

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.812

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.629

GnomAD3 exomes AF: 0.666 AC: 166086 AN: 249254 Hom.: 56694 AF XY: 0.678 AC XY: 91474 AN XY: 134836

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.379

Gnomad SAS exome AF: 0.765

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.703

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.691 AC: 1009671 AN: 1460730 Hom.: 351587 Cov.: 49 AF XY: 0.694 AC XY: 504628 AN XY: 726714

Gnomad4 AFR exome AF: 0.553

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.708

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.770

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.699

Gnomad4 OTH exome AF: 0.682

GnomAD4 genome AF: 0.640 AC: 97237 AN: 152036 Hom.: 31637 Cov.: 33 AF XY: 0.639 AC XY: 47457 AN XY: 74322

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.721

Gnomad4 NFE AF: 0.693

Gnomad4 OTH AF: 0.631

Alfa AF: 0.666 Hom.: 12419

Bravo AF: 0.622

Asia WGS AF: 0.634 AC: 2205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

Hyperphosphatasia with intellectual disability syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.27
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.080		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: rs2247862; hg19: chr17-37829129; COSMIC: COSV54092907; COSMIC: COSV54092907;