NM_002641.4:c.1403A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002641.4(PIGA):c.1403A>G(p.Tyr468Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,203,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 4 hem. )

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.109

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):

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023509651).

BP6

Variant X-15321558-T-C is Benign according to our data. Variant chrX-15321558-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1601074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 17 Unknown,XL,AD 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.1403A>G	p.Tyr468Cys	missense	Exon 6 of 6	NP_002632.1	P37287-1
PIGA	NM_001440789.1		c.1496A>G	p.Tyr499Cys	missense	Exon 7 of 7	NP_001427718.1
PIGA	NM_001440790.1		c.794A>G	p.Tyr265Cys	missense	Exon 6 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.1403A>G	p.Tyr468Cys	missense	Exon 6 of 6	ENSP00000369820.3	P37287-1
PIGA	ENST00000542278.6	TSL:5	c.1403A>G	p.Tyr468Cys	missense	Exon 6 of 6	ENSP00000442653.2	P37287-1
PIGA	ENST00000482148.6	TSL:5	c.896A>G	p.Tyr299Cys	missense	Exon 5 of 5	ENSP00000489528.1	P37287-2

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112492

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:

0.000277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

183452

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1091398

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

356898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26263

American (AMR)

AF:

0.0000284

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19340

East Asian (EAS)

AF:

0.000431

AC:

AN:

30177

South Asian (SAS)

AF:

0.00

AC:

AN:

53989

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00000359

AC:

AN:

835874

Other (OTH)

AF:

0.00

AC:

AN:

45891

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00000889

AC:

AN:

112545

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34687

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30975

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.000277

AC:

AN:

3605

South Asian (SAS)

AF:

0.00

AC:

AN:

2784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6185

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53301

Other (OTH)

AF:

0.00

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

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

0.061

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.085

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.41

M_CAP

Benign

0.0041

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.11

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.98

REVEL

Benign

0.0050

Sift

Benign

0.18

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.12

MutPred

0.22

Loss of disorder (P = 0.0998)

MVP

0.24

MPC

0.70

ClinPred

0.017

GERP RS

-3.2

Varity_R

0.070

gMVP

0.64

Mutation Taster

=96/4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over