X-15321541-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002641.4(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 NM_002641.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.590

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]

ACMG classification

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 GnomAd at 43 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.1420G>A	p.Gly474Arg	missense_variant	6/6	ENST00000333590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.1420G>A	p.Gly474Arg	missense_variant	6/6	1	NM_002641.4	P1

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 155 AN: 112425 Hom.: 0 Cov.: 23 AF XY: 0.00124 AC XY: 43 AN XY: 34571

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: 70 AN: 183338 Hom.: 1 AF XY: 0.000324 AC XY: 22 AN XY: 67830

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.: 1 Cov.: 28 AF XY: 0.000140 AC XY: 50 AN XY: 358241

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.: 0 Cov.: 23 AF XY: 0.00127 AC XY: 44 AN XY: 34633

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.: 8

Bravo AF: 0.00170

ESP6500AA AF: 0.00678 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	T
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	N
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
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	T
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

Other links and lift over

dbSNP: rs61760986; hg19: chrX-15339663;