chrX-15321217-TATA-T

Variant names:

• chrX-15321217-TATA-T
• rs753691551
• NM_002641.4:c.*286_*288delTAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002641.4(PIGA):​c.*286_*288delTAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 201,960 control chromosomes in the GnomAD database, including 8 homozygotes. There are 193 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., 181 hem., cov: 23)
  • Exomes 𝑓: 0.00094 (0 hom. 12 hem.)
• Consequence: PIGA NM_002641.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.75
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-15321217-TATA-T is Benign according to our data. Variant chrX-15321217-TATA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1185707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00568 (635/111878) while in subpopulation AFR AF = 0.0197 (606/30794). AF 95% confidence interval is 0.0184. There are 8 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 635 Unknown,XL,AD 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.*286_*288delTAT		3_prime_UTR	Exon 6 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.*286_*288delTAT		3_prime_UTR	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.*286_*288delTAT		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.*286_*288delTAT		3_prime_UTR	Exon 6 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.*286_*288delTAT		3_prime_UTR	Exon 6 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000637296.1	TSL:5	c.*286_*288delTAT		3_prime_UTR	Exon 7 of 7	ENSP00000490545.1	B3KUV7

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 633 AN: 111823 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

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: 0.0000564

Gnomad OTH AF: 0.00198

GnomAD4 exome AF: 0.000944 AC: 85 AN: 90082 Hom.: 0 AF XY: 0.000680 AC XY: 12 AN XY: 17644

African (AFR) AF: 0.0202 AC: 67 AN: 3313

American (AMR) AF: 0.00160 AC: 7 AN: 4368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3032

East Asian (EAS) AF: 0.00 AC: 0 AN: 7069

South Asian (SAS) AF: 0.00 AC: 0 AN: 3877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 379

European-Non Finnish (NFE) AF: 0.0000173 AC: 1 AN: 57709

Other (OTH) AF: 0.00168 AC: 10 AN: 5965

GnomAD4 genome AF: 0.00568 AC: 635 AN: 111878 Hom.: 8 Cov.: 23 AF XY: 0.00531 AC XY: 181 AN XY: 34064

African (AFR) AF: 0.0197 AC: 606 AN: 30794

American (AMR) AF: 0.00218 AC: 23 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53153

Other (OTH) AF: 0.00196 AC: 3 AN: 1531

Alfa AF: 0.00541 Hom.: 16

Bravo AF: 0.00667

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
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: rs753691551; hg19: chrX-15339339;