Variant 11-3811356-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_014489.4(PGAP2):c.97G>A(p.Ala33Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PGAP2
NM_014489.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.90

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:

LOC124902618 (HGNC:):

LOC124902618 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 26 pathogenic changes around while only 5 benign (84%) in NM_014489.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP2	NM_014489.4 linkuse as main transcript	c.97G>A	p.Ala33Thr	missense_variant	2/7	ENST00000278243.9
LOC124902618	XR_007062559.1 linkuse as main transcript	n.361C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP2	ENST00000278243.9 linkuse as main transcript	c.97G>A	p.Ala33Thr	missense_variant	2/7	1	NM_014489.4	A1	Q9UHJ9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2020

The c.97G>A (p.A33T) alteration is located in exon 2 (coding exon 1) of the PGAP2 gene. This alteration results from a G to A substitution at nucleotide position 97, causing the alanine (A) at amino acid position 33 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PGAP2 c.97G>A alteration was not observed, with coverage at this position. This amino acid position is well conserved in available vertebrate species. The p.A33T alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Micrognathia;C0344482:Hypoplasia of the corpus callosum;C0795690:Congenital omphalocele

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Mar 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.47

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

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.3

.;.;.;.;L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;N;N;N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.23

Sift

Benign

0.16

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

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D;D;D

Polyphen

0.99

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

Vest4

0.58

MutPred

0.72

Gain of catalytic residue at F93 (P = 0.1686);Gain of catalytic residue at F93 (P = 0.1686);.;.;.;.;.;.;.;

MVP

0.53

MPC

1.0

ClinPred

0.96

GERP RS

4.9

Varity_R

0.18

gMVP

0.68

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