X-15335513-T-A

Variant names:

• chrX-15335513-T-A
• rs985880836
• NM_002641.4:c.-75A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002641.4(PIGA):​c.-75A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 863,042 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000012 (0 hom. 0 hem.)
• Consequence: PIGA NM_002641.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-75A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_002632.1	P37287-1
	PIGA	NM_002641.4	MANE Select	c.-75A>T		5_prime_UTR	Exon 1 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.-75A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001427718.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.-75A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.-75A>T		5_prime_UTR	Exon 1 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000637296.1	TSL:5	c.-446A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000490545.1	B3KUV7

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000116 AC: 1 AN: 863042 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 265800

African (AFR) AF: 0.00 AC: 0 AN: 18677

American (AMR) AF: 0.00 AC: 0 AN: 8365

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11735

East Asian (EAS) AF: 0.00 AC: 0 AN: 20644

South Asian (SAS) AF: 0.00 AC: 0 AN: 23009

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18939

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.00000138 AC: 1 AN: 722950

Other (OTH) AF: 0.00 AC: 0 AN: 35385

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.95
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.1	T
PhyloP100		0.19
Sift4G	Pathogenic	0.0	D
Vest4		0.65
MutPred		0.56		Loss of disorder (P = 0.2078)
ClinPred		0.86	D
GERP RS		2.5
PromoterAI		-0.28	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=124/76	polymorphism

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: rs985880836; hg19: chrX-15353635; COSMIC: COSV109429010; COSMIC: COSV109429010;