Variant X-15331701-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_002641.4(PIGA):c.230G>A(p.Arg77Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,076 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

PIGA
NM_002641.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.49

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant X-15331701-C-T is Pathogenic according to our data. Variant chrX-15331701-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810512.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PIGA	NM_002641.4 linkuse as main transcript	c.230G>A	p.Arg77Gln	missense_variant	2/6	ENST00000333590.6	NP_002632.1
PIGA	NM_020473.3 linkuse as main transcript	c.13+3800G>A		intron_variant			NP_065206.3
PIGA	NR_033835.1 linkuse as main transcript	n.346G>A		non_coding_transcript_exon_variant	2/6
PIGA	NR_033836.1 linkuse as main transcript	n.173+173G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6 linkuse as main transcript	c.230G>A	p.Arg77Gln	missense_variant	2/6	1	NM_002641.4	ENSP00000369820	P1	P37287-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

112493

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34647

FAILED QC

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098076

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

112493

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34647

Gnomad4 AFR

AF:

0.00

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2017

- -

Neurodevelopmental disorder with epilepsy and hemochromatosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;D;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

.;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.5

M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.6

D;.;.;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0050

D;.;.;.

Sift4G

Uncertain

0.011

D;D;D;.

Polyphen

1.0

D;D;P;.

Vest4

0.70

MutPred

0.85

Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);

MVP

0.94

MPC

1.6

ClinPred

1.0

GERP RS

5.2

Varity_R

0.96

gMVP

0.84

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