chrX-15331699-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2

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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

multiple congenital anomalies-hypotonia-seizures syndrome 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ferro-cerebro-cutaneous syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
paroxysmal nocturnal hemoglobinuria
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

PIGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_002641.4

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 VariationId is 211904.

BS2

High AC in GnomAdExome4 at 34 Unknown,XL,AD 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

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183487

AF XY:

0.0000147

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 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

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.0000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000392

AC:

AN:

842015

Other (OTH)

AF:

0.00

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

(source)

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;.

PhyloP100

4.6

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

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over