rs34422225

Positions:

chrX-15331876-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/18 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:4

Conservation

PhyloP100: 0.421

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 -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 id is 488577.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.

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 id is 380857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-15331876-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIGA	NM_002641.4 linkuse as main transcript	c.55C>T	p.Arg19Trp	missense_variant	2/6	ENST00000333590.6
PIGA	NM_020473.3 linkuse as main transcript	c.13+3625C>T		intron_variant
PIGA	NR_033835.1 linkuse as main transcript	n.171C>T		non_coding_transcript_exon_variant	2/6
PIGA	NR_033836.1 linkuse as main transcript	n.171C>T		splice_region_variant, non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6 linkuse as main transcript	c.55C>T	p.Arg19Trp	missense_variant	2/6	1	NM_002641.4	P1	P37287-1

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

3437

AN:

111781

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

939

AN XY:

33957

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

GnomAD3 exomes

AF:

0.0301

AC:

5495

AN:

182503

Hom.:

AF XY:

0.0312

AC XY:

2094

AN XY:

67039

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 SAS exome

AF:

0.0272

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

Gnomad4 AFR exome

AF:

0.0266

Gnomad4 AMR exome

AF:

0.0189

Gnomad4 ASJ exome

AF:

0.0851

Gnomad4 EAS exome

AF:

0.000431

Gnomad4 SAS exome

AF:

0.0303

Gnomad4 FIN exome

AF:

0.0178

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0356

GnomAD4 genome

AF:

0.0307

AC:

3435

AN:

111831

Hom.:

Cov.:

AF XY:

0.0275

AC XY:

937

AN XY:

34017

show subpopulations

Gnomad4 AFR

AF:

0.0250

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.0747

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.0249

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.0383

Gnomad4 OTH

AF:

0.0348

Alfa

AF:

0.0395

Hom.:

1871

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 31, 2017

- -

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

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;.

MutationTaster

Benign

1.0

P;P;P

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

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