rs202161781

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002641.4(PIGA):c.877A>G(p.Lys293Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000917 in 1,199,931 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K293K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.61

Publications

0 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):

complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
multiple congenital anomalies-hypotonia-seizures syndrome 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09290597).

BP6

Variant X-15325124-T-C is Benign according to our data. Variant chrX-15325124-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471953.

BS2

High AC in GnomAdExome4 at 7 AD,XL,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGA	NM_002641.4	MANE Select	c.877A>G	p.Lys293Glu	missense	Exon 4 of 6	NP_002632.1	P37287-1
PIGA	NM_001440789.1		c.970A>G	p.Lys324Glu	missense	Exon 5 of 7	NP_001427718.1
PIGA	NM_001440790.1		c.268A>G	p.Lys90Glu	missense	Exon 4 of 6	NP_001427719.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGA	ENST00000333590.6	TSL:1 MANE Select	c.877A>G	p.Lys293Glu	missense	Exon 4 of 6	ENSP00000369820.3	P37287-1
PIGA	ENST00000542278.6	TSL:5	c.877A>G	p.Lys293Glu	missense	Exon 4 of 6	ENSP00000442653.2	P37287-1
PIGA	ENST00000482148.6	TSL:5	c.370A>G	p.Lys124Glu	missense	Exon 3 of 5	ENSP00000489528.1	P37287-2

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112124

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000578

AC:

AN:

173079

AF XY:

0.0000170

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000643

AC:

AN:

1087807

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

354329

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26034

American (AMR)

AF:

0.00

AC:

AN:

33447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18994

East Asian (EAS)

AF:

0.00

AC:

AN:

29898

South Asian (SAS)

AF:

0.00

AC:

AN:

51885

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.00000836

AC:

AN:

837467

Other (OTH)

AF:

0.00

AC:

AN:

45664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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

AF:

0.0000357

AC:

AN:

112124

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30855

American (AMR)

AF:

0.00

AC:

AN:

10514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53238

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

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:

0.000583

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Multiple congenital anomalies-hypotonia-seizures syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.035

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.64

PhyloP100

4.6

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.51

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.34

MVP

0.65

MPC

0.79

ClinPred

0.21

GERP RS

4.8

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.40

gMVP

0.57

Mutation Taster

=59/41

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over