X-15321541-C-T

Position:

chrX-15321541-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000333590.6(PIGA):c.1420G>A(p.Gly474Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,205,066 control chromosomes in the GnomAD database, including 1 homozygotes. There are 94 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G474V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., 44 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 1 hom. 50 hem. )

Consequence

PIGA
ENST00000333590.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.590

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002711445).

BP6

Variant X-15321541-C-T is Benign according to our data. Variant chrX-15321541-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 508489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-15321541-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 44 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGA	NM_002641.4 linkuse as main transcript	c.1420G>A	p.Gly474Arg	missense_variant	6/6	ENST00000333590.6	NP_002632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6 linkuse as main transcript	c.1420G>A	p.Gly474Arg	missense_variant	6/6	1	NM_002641.4	ENSP00000369820	P1	P37287-1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

155

AN:

112425

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

34571

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.000659

GnomAD3 exomes

AF:

0.000382

AC:

AN:

183338

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

67830

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000143

AC:

156

AN:

1092589

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

358241

show subpopulations

Gnomad4 AFR exome

AF:

0.00544

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000131

GnomAD4 genome

AF:

0.00139

AC:

156

AN:

112477

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

AN XY:

34633

show subpopulations

Gnomad4 AFR

AF:

0.00494

Gnomad4 AMR

AF:

0.000189

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:

0.000651

Alfa

AF:

0.000150

Hom.:

Bravo

AF:

0.00170

ESP6500AA

AF:

0.00678

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2016

This alteration is classified as likely 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.0050

DANN

Benign

0.20

DEOGEN2

Benign

0.10

T;T;T;.;.

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.61

.;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;N;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.14

N;.;.;.;.

REVEL

Benign

0.0070

Sift

Benign

0.65

T;.;.;.;.

Sift4G

Benign

0.70

T;T;.;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.060

MutPred

0.10

Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);.;.;.;

MVP

0.12

MPC

0.67

ClinPred

0.0015

GERP RS

-8.2

Varity_R

0.045

gMVP

0.44

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

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