rs2247862

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033419.5(PGAP3):c.900-10T>C variant causes a 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 intron

Scores

Splicing: ADA: 0.0002155

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.73

Publications

27 publications found

Variant links:

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

PGAP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PGAP3	NM_033419.5 link	c.900-10T>C		intron_variant	Intron 7 of 7	ENST00000300658.9	NP_219487.3	Q96FM1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9 link	c.900-10T>C		intron_variant	Intron 7 of 7	1	NM_033419.5	ENSP00000300658.4		Q96FM1-1

Frequencies

GnomAD3 genomes

AF:

0.639

AC:

97147

AN:

151920

Hom.:

31609

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.666

AC:

166086

AN:

249254

AF XY:

0.678

show subpopulations

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 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.:

AF XY:

0.694

AC XY:

504628

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.553

AC:

18511

AN:

33458

American (AMR)

AF:

0.606

AC:

27047

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.708

AC:

18493

AN:

26120

East Asian (EAS)

AF:

0.455

AC:

18052

AN:

39668

South Asian (SAS)

AF:

0.770

AC:

66382

AN:

86206

European-Finnish (FIN)

AF:

0.719

AC:

38384

AN:

53366

Middle Eastern (MID)

AF:

0.770

AC:

4415

AN:

5732

European-Non Finnish (NFE)

AF:

0.699

AC:

777206

AN:

1111156

Other (OTH)

AF:

0.682

AC:

41181

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

16395

32791

49186

65582

81977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19582

39164

58746

78328

97910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.640

AC:

97237

AN:

152036

Hom.:

31637

Cov.:

AF XY:

0.639

AC XY:

47457

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.557

AC:

23060

AN:

41420

American (AMR)

AF:

0.593

AC:

9053

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2427

AN:

3470

East Asian (EAS)

AF:

0.409

AC:

2114

AN:

5164

South Asian (SAS)

AF:

0.738

AC:

3560

AN:

4824

European-Finnish (FIN)

AF:

0.721

AC:

7644

AN:

10604

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.693

AC:

47107

AN:

67960

Other (OTH)

AF:

0.631

AC:

1332

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1804

3607

5411

7214

9018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.661

Hom.:

13254

Bravo

AF:

0.622

Asia WGS

AF:

0.634

AC:

2205

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperphosphatasia with intellectual disability syndrome 4

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.27

(source)

DANN

Benign

0.71

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over