rs62185645

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024989.4(PGAP1):c.1753C>G(p.Gln585Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0054 in 1,606,892 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q585Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 31 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.74

Publications

8 publications found

Variant links:

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

PGAP1 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 42
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive spastic paraplegia type 67
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PGAP1 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 (MetaRNN=0.0069019794).

BP6

Variant 2-196870955-G-C is Benign according to our data. Variant chr2-196870955-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436291.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 = 0.00396 (603/152166) while in subpopulation NFE AF = 0.0069 (469/68012). AF 95% confidence interval is 0.00638. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP1	NM_024989.4 link	c.1753C>G	p.Gln585Glu	missense_variant	Exon 19 of 27	ENST00000354764.9	NP_079265.2	Q75T13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9 link	c.1753C>G	p.Gln585Glu	missense_variant	Exon 19 of 27	1	NM_024989.4	ENSP00000346809.3		Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

603

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00303

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00690

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00431

AC:

1079

AN:

250400

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00476

Gnomad NFE exome

AF:

0.00774

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00555

AC:

8076

AN:

1454726

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

3836

AN XY:

724130

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33328

American (AMR)

AF:

0.00148

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.00491

AC:

261

AN:

53130

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00665

AC:

7359

AN:

1106126

Other (OTH)

AF:

0.00580

AC:

349

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

335

669

1004

1338

1673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.00396

AC:

603

AN:

152166

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

296

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41510

American (AMR)

AF:

0.00321

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00303

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00690

AC:

469

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00600

Hom.:

Bravo

AF:

0.00411

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00507

AC:

616

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00705

EpiControl

AF:

0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PGAP1: BP4, BS2 -

Jul 19, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal recessive 42

Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 02, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.00047

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0069

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PhyloP100

5.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.14

Sift

Benign

0.41

T;T

Sift4G

Uncertain

0.032

D;T

Polyphen

0.26

B;B

Vest4

0.51

MVP

0.65

MPC

0.27

ClinPred

0.0090

GERP RS

4.6

Varity_R

0.16

gMVP

0.75

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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