rs148660178

Variant names:

• chrX-15321466-C-T
• rs148660178
• NM_002641.4:c.*40G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002641.4(PIGA):​c.*40G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,130,223 control chromosomes in the GnomAD database, including 178 homozygotes. There are 1,846 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (84 hom., 742 hem., cov: 23)
  • Exomes 𝑓: 0.0042 (94 hom. 1104 hem.)
• Consequence: PIGA NM_002641.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.164
• Publications: 1 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, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-15321466-C-T is Benign according to our data. Variant chrX-15321466-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

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.*40G>A		3_prime_UTR	Exon 6 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.*40G>A		3_prime_UTR	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.*40G>A		3_prime_UTR	Exon 6 of 6	NP_001427719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.*40G>A		3_prime_UTR	Exon 6 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.*40G>A		3_prime_UTR	Exon 6 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000482148.6	TSL:5	c.*40G>A		3_prime_UTR	Exon 5 of 5	ENSP00000489528.1	P37287-2

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 2872 AN: 112190 Hom.: 84 Cov.: 23

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00493

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.000495

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.0265

GnomAD2 exomes AF: 0.00857 AC: 1412 AN: 164743 AF XY: 0.00654

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.00556

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000534

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00424 AC: 4314 AN: 1017979 Hom.: 94 Cov.: 20 AF XY: 0.00364 AC XY: 1104 AN XY: 303509

African (AFR) AF: 0.0909 AC: 2205 AN: 24268

American (AMR) AF: 0.00571 AC: 184 AN: 32239

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 75 AN: 17932

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29750

South Asian (SAS) AF: 0.000618 AC: 31 AN: 50177

European-Finnish (FIN) AF: 0.000476 AC: 19 AN: 39928

Middle Eastern (MID) AF: 0.00709 AC: 26 AN: 3665

European-Non Finnish (NFE) AF: 0.00184 AC: 1429 AN: 776906

Other (OTH) AF: 0.00798 AC: 344 AN: 43114

GnomAD4 genome AF: 0.0257 AC: 2886 AN: 112244 Hom.: 84 Cov.: 23 AF XY: 0.0215 AC XY: 742 AN XY: 34440

African (AFR) AF: 0.0831 AC: 2564 AN: 30864

American (AMR) AF: 0.0113 AC: 120 AN: 10618

Ashkenazi Jewish (ASJ) AF: 0.00493 AC: 13 AN: 2636

East Asian (EAS) AF: 0.000277 AC: 1 AN: 3606

South Asian (SAS) AF: 0.00108 AC: 3 AN: 2774

European-Finnish (FIN) AF: 0.000495 AC: 3 AN: 6063

Middle Eastern (MID) AF: 0.0185 AC: 4 AN: 216

European-Non Finnish (NFE) AF: 0.00259 AC: 138 AN: 53250

Other (OTH) AF: 0.0262 AC: 40 AN: 1528

Alfa AF: 0.0103 Hom.: 85

Bravo AF: 0.0293

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.32
PhyloP100		-0.16
Mutation Taster		=100/0	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: rs148660178; hg19: chrX-15339588;