rs776182358

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_002641.4(PIGA):c.232A>G(p.Lys78Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,098,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000031 ( 0 hom. 13 hem. )

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.58

Variant links:

Genes affected

PIGA (HGNC:8957): (phosphatidylinositol glycan anchor biosynthesis class A) This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]

PIGA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-15331699-T-C is Benign according to our data. Variant chrX-15331699-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211904.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGA	NM_002641.4 link	c.232A>G	p.Lys78Glu	missense_variant	Exon 2 of 6	ENST00000333590.6	NP_002632.1	P37287-1A0A2K4ZA02
PIGA	NM_020473.3 link	c.13+3802A>G		intron_variant	Intron 1 of 4		NP_065206.3	P37287-3
PIGA	NR_033835.1 link	n.348A>G		non_coding_transcript_exon_variant	Exon 2 of 6
PIGA	NR_033836.1 link	n.173+175A>G		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6 link	c.232A>G	p.Lys78Glu	missense_variant	Exon 2 of 6	1	NM_002641.4	ENSP00000369820.3		P37287-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183487

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67919

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1098124

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000392

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple congenital anomalies-hypotonia-seizures syndrome 2

Benign:1

Nov 26, 2018

Clinical and Biomedical Sciences, University of Exeter

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Ventriculomegaly and absent corpus callosum. PIGA deficient B lymphoblasts (JY5) were transfected with wild-type or mutant PIGA expressing plasmids driven by strong, mild or weak promoters. Expression of GPI anchored proteins (CD59/DAF/FLAER) was analysed by FACS. Mutant PIGA could rescue the surface expression of GPI-APs at a similar level to wild-type PIGA. Western blot analysis showed expression of mutant PIGA protein was similar to wild-type. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.7

L;L;L;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.96

N;.;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.14

T;.;.;.

Sift4G

Benign

0.28

T;T;T;.

Polyphen

0.92

P;P;D;.

Vest4

0.48

MutPred

0.45

Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);

MVP

0.81

MPC

1.2

ClinPred

0.27

GERP RS

6.1

Varity_R

0.70

gMVP

0.92

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