rs758863767

Positions:

chrX-15331839-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_002641.4(PIGA):c.92G>A(p.Arg31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,210,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. R31C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000022 ( 0 hom. 6 hem. )

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.46

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_002641.4

BP4

Computational evidence support a benign effect (MetaRNN=0.049393356).

BP6

Variant X-15331839-C-T is Benign according to our data. Variant chrX-15331839-C-T is described in ClinVar as [Benign]. Clinvar id is 582423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIGA	NM_002641.4 linkuse as main transcript	c.92G>A	p.Arg31His	missense_variant	2/6	ENST00000333590.6
PIGA	NM_020473.3 linkuse as main transcript	c.13+3662G>A		intron_variant
PIGA	NR_033835.1 linkuse as main transcript	n.208G>A		non_coding_transcript_exon_variant	2/6
PIGA	NR_033836.1 linkuse as main transcript	n.173+35G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6 linkuse as main transcript	c.92G>A	p.Arg31His	missense_variant	2/6	1	NM_002641.4	P1	P37287-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34213

show subpopulations

Gnomad AFR

AF:

0.0000976

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000600

AC:

AN:

183473

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67909

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1098085

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363441

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.000310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34213

show subpopulations

Gnomad4 AFR

AF:

0.0000976

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

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

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.0020

DANN

Benign

0.83

DEOGEN2

Benign

0.21

T;T;.;.

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.28

.;T;T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;M;M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.0

N;.;.;.

REVEL

Benign

0.062

Sift

Benign

0.12

T;.;.;.

Sift4G

Benign

0.065

T;T;T;.

Polyphen

0.0

B;B;B;.

Vest4

0.12

MVP

0.35

MPC

0.70

ClinPred

0.067

GERP RS

-11

Varity_R

0.024

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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