17-39684607-G-C

Position:

chr17-39684607-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.51

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 links:

PGAP3 (HGNC:):

PGAP3 links:

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ACMG classification

Classification made for transcript

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 16 pathogenic changes around while only 1 benign (94%) 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 GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAP3	NM_033419.5 linkuse as main transcript	c.422C>G	p.Ala141Gly	missense_variant	3/8	ENST00000300658.9	NP_219487.3	Q96FM1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9 linkuse as main transcript	c.422C>G	p.Ala141Gly	missense_variant	3/8	1	NM_033419.5	ENSP00000300658.4		Q96FM1-1

Frequencies

GnomAD3 genomes

AF:

0.00753

AC:

1146

AN:

152230

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00813

AC XY:

1091

AN XY:

134234

show subpopulations

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.:

Cov.:

AF XY:

0.00802

AC XY:

5823

AN XY:

725832

show subpopulations

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.:

Cov.:

AF XY:

0.00835

AC XY:

622

AN XY:

74490

show subpopulations

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.:

Bravo

AF:

0.00463

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00814

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PGAP3: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;T;.;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;T

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

.;L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

.;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.28

.;T;D;.

Sift4G

Benign

0.49

T;T;T;.

Polyphen

0.31

.;B;.;.

Vest4

0.66

MVP

0.64

MPC

0.46

ClinPred

0.022

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over