Variant 11-3825024-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_014489.4(PGAP2):c.713G>A(p.Arg238His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PGAP2
NM_014489.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.59

Variant links:

Genes affected

PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

PGAP2 links:

PGAP2 (HGNC:):

PGAP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Post-GPI attachment to proteins factor 2 (size 253) in uniprot entity PGAP2_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_014489.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-3825024-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.19161728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAP2	NM_014489.4 linkuse as main transcript	c.713G>A	p.Arg238His	missense_variant	6/7	ENST00000278243.9	NP_055304.1	Q9UHJ9-2A0A024RCC6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP2	ENST00000278243.9 linkuse as main transcript	c.713G>A	p.Arg238His	missense_variant	6/7	1	NM_014489.4	ENSP00000278243.4		Q9UHJ9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;.;.;.;.;.;.;T;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.78

T;T;.;.;.;.;T;T;T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.2

.;.;.;.;.;.;.;.;M;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

N;N;N;.;.;.;.;N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.017

D;D;.;.;.;.;.;D;T;D;T;T

Sift4G

Benign

0.079

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.99

D;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.29

MutPred

0.55

Loss of MoRF binding (P = 0.0298);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.57

MPC

0.46

ClinPred

0.49

GERP RS

4.3

Varity_R

0.060

gMVP

0.35

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over