rs34422225

Variant names:

• chrX-15331876-G-A
• rs34422225
• NM_002641.4:c.55C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

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. 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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.421
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• multiple congenital anomalies-hypotonia-seizures syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ferro-cerebro-cutaneous syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal nocturnal hemoglobinuria

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 488577.
• 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 VariationId is 380857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3435 AD,XL,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	NM_002641.4	MANE Select	c.55C>T	p.Arg19Trp	missense	Exon 2 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.55C>T	p.Arg19Trp	missense	Exon 2 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.14-3563C>T		intron	N/A	NP_001427719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.55C>T	p.Arg19Trp	missense	Exon 2 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000637296.1	TSL:5	c.-317C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000490545.1	B3KUV7
	PIGA	ENST00000634640.1	TSL:5	c.-233C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000489083.1	A0A0U1RQM9

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 3437 AN: 111781 Hom.: 45 Cov.: 23

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

GnomAD2 exomes AF: 0.0301 AC: 5495 AN: 182503 AF XY: 0.0312

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 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.: 30 AF XY: 0.0349 AC XY: 12645 AN XY: 362500

African (AFR) AF: 0.0266 AC: 701 AN: 26388

American (AMR) AF: 0.0189 AC: 666 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.0851 AC: 1646 AN: 19341

East Asian (EAS) AF: 0.000431 AC: 13 AN: 30196

South Asian (SAS) AF: 0.0303 AC: 1640 AN: 54053

European-Finnish (FIN) AF: 0.0178 AC: 720 AN: 40497

Middle Eastern (MID) AF: 0.0419 AC: 173 AN: 4128

European-Non Finnish (NFE) AF: 0.0371 AC: 31196 AN: 841277

Other (OTH) AF: 0.0356 AC: 1638 AN: 46047

GnomAD4 genome AF: 0.0307 AC: 3435 AN: 111831 Hom.: 45 Cov.: 23 AF XY: 0.0275 AC XY: 937 AN XY: 34017

African (AFR) AF: 0.0250 AC: 769 AN: 30767

American (AMR) AF: 0.0218 AC: 230 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 198 AN: 2649

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3578

South Asian (SAS) AF: 0.0249 AC: 66 AN: 2648

European-Finnish (FIN) AF: 0.0119 AC: 72 AN: 6044

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.0383 AC: 2035 AN: 53165

Other (OTH) AF: 0.0348 AC: 53 AN: 1524

Alfa AF: 0.0388 Hom.: 1941

Bravo AF: 0.0319

TwinsUK AF: 0.0391 AC: 145

ALSPAC AF: 0.0312 AC: 90

ESP6500AA AF: 0.0253 AC: 97

ESP6500EA AF: 0.0375 AC: 252

ExAC AF: 0.0314 AC: 3812

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.3
DANN	Benign	0.75
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.42
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.059
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.58
ClinPred		0.0018	T
GERP RS		0.89
Varity_R		0.057
gMVP		0.59
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34422225; hg19: chrX-15349998; COSMIC: COSV61237623; COSMIC: COSV61237623;