rs34422225

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_002641.4(PIGA):c.55C>T(p.Arg19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,208,937 control chromosomes in the GnomAD database, including 580 homozygotes. There are 13,582 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.031 ( 45 hom., 937 hem., cov: 23)

Exomes 𝑓: 0.035 ( 535 hom. 12645 hem. )

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.421

Publications

20 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: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-15331875-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488577.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021357834).

BP6

Variant X-15331876-G-A is Benign according to our data. Variant chrX-15331876-G-A is described in ClinVar as Benign. ClinVar VariationId is 380857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0307 (3435/111831) while in subpopulation NFE AF = 0.0383 (2035/53165). AF 95% confidence interval is 0.0369. There are 45 homozygotes in GnomAd4. There are 937 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 3435 Unknown,XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGA	NM_002641.4 link	c.55C>T	p.Arg19Trp	missense_variant	Exon 2 of 6	ENST00000333590.6	NP_002632.1	P37287-1A0A2K4ZA02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6 link	c.55C>T	p.Arg19Trp	missense_variant	Exon 2 of 6	1	NM_002641.4	ENSP00000369820.3		P37287-1

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

3437

AN:

111781

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0250

Gnomad AMI

AF:

0.00586

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0747

Gnomad EAS

AF:

0.00111

Gnomad SAS

AF:

0.0256

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0168

Gnomad NFE

AF:

0.0383

Gnomad OTH

AF:

0.0352

GnomAD2 exomes

AF:

0.0301

AC:

5495

AN:

182503

AF XY:

0.0312

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0837

Gnomad EAS exome

AF:

0.000722

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0381

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0350

AC:

38393

AN:

1097106

Hom.:

535

Cov.:

AF XY:

0.0349

AC XY:

12645

AN XY:

362500

show subpopulations

African (AFR)

AF:

0.0266

AC:

701

AN:

26388

American (AMR)

AF:

0.0189

AC:

666

AN:

35179

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

1646

AN:

19341

East Asian (EAS)

AF:

0.000431

AC:

AN:

30196

South Asian (SAS)

AF:

0.0303

AC:

1640

AN:

54053

European-Finnish (FIN)

AF:

0.0178

AC:

720

AN:

40497

Middle Eastern (MID)

AF:

0.0419

AC:

173

AN:

4128

European-Non Finnish (NFE)

AF:

0.0371

AC:

31196

AN:

841277

Other (OTH)

AF:

0.0356

AC:

1638

AN:

46047

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1329

2659

3988

5318

6647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1178

2356

3534

4712

5890

<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:

0.0307

AC:

3435

AN:

111831

Hom.:

Cov.:

AF XY:

0.0275

AC XY:

937

AN XY:

34017

show subpopulations

African (AFR)

AF:

0.0250

AC:

769

AN:

30767

American (AMR)

AF:

0.0218

AC:

230

AN:

10556

Ashkenazi Jewish (ASJ)

AF:

0.0747

AC:

198

AN:

2649

East Asian (EAS)

AF:

0.00112

AC:

AN:

3578

South Asian (SAS)

AF:

0.0249

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.0119

AC:

AN:

6044

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0383

AC:

2035

AN:

53165

Other (OTH)

AF:

0.0348

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

127

255

382

510

637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0388

Hom.:

1941

Bravo

AF:

0.0319

TwinsUK

AF:

0.0391

AC:

145

ALSPAC

AF:

0.0312

AC:

ESP6500AA

AF:

0.0253

AC:

ESP6500EA

AF:

0.0375

AC:

252

ExAC

AF:

0.0314

AC:

3812

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 31, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 15, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Multiple congenital anomalies-hypotonia-seizures syndrome 2

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 27, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.92

CADD

Benign

9.3

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.16

T;T;.;.

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.28

.;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N;N;.

PhyloP100

0.42

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.72

N;.;.;.

REVEL

Benign

0.059

Sift

Benign

0.19

T;.;.;.

Sift4G

Benign

0.19

T;T;T;.

Polyphen

0.0

B;B;B;.

Vest4

0.065

MPC

0.58

ClinPred

0.0018

GERP RS

0.89

Varity_R

0.057

gMVP

0.59

Mutation Taster

=96/4

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over