X-15321540-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002641.4(PIGA):c.1421G>T(p.Gly474Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,204,475 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 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. G474R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000078 (0 hom. 31 hem.)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.45

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07598513).
• BP6: Variant X-15321540-C-A is Benign according to our data. Variant chrX-15321540-C-A is described in ClinVar as [Benign]. Clinvar id is 791074.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-15321540-C-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.1421G>T	p.Gly474Val	missense_variant	6/6	ENST00000333590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.1421G>T	p.Gly474Val	missense_variant	6/6	1	NM_002641.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112337 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34479

Gnomad AFR AF: 0.0000324

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 21 AN: 183290 Hom.: 0 AF XY: 0.000192 AC XY: 13 AN XY: 67796

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

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: 0.000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000778 AC: 85 AN: 1092138 Hom.: 0 Cov.: 28 AF XY: 0.0000866 AC XY: 31 AN XY: 357812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000944

Gnomad4 OTH exome AF: 0.000131

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112337 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34479

Gnomad4 AFR AF: 0.0000324

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: 0.0000375

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

May 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.011
Dann	Benign	0.29
DEOGEN2	Benign	0.13	T;T;T;.;.
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.076	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.16	N;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.18	T;.;.;.;.
Sift4G	Benign	0.26	T;T;.;T;T
Polyphen		0.026	B;B;.;.;B
Vest4		0.084
MVP		0.23
MPC		0.71
ClinPred		0.044	T
GERP RS		-4.3
Varity_R		0.056
gMVP		0.54

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: rs142772459; hg19: chrX-15339662;