rs202201866

Variant names:

• chrX-15321420-CA-C
• rs202201866
• NM_002641.4:c.*85delT

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.*85delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 867,778 control chromosomes in the GnomAD database, including 16 homozygotes. There are 287 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., 174 hem., cov: 22)
  • Exomes 𝑓: 0.00065 (7 hom. 113 hem.)
• Consequence: PIGA NM_002641.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.379
• 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, 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 -10 ACMG points.

• BP6: Variant X-15321420-CA-C is Benign according to our data. Variant chrX-15321420-CA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1212595.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0056 (628/112085) while in subpopulation AFR AF = 0.0194 (599/30866). AF 95% confidence interval is 0.0181. There are 9 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 628 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.*85delT		3_prime_UTR	Exon 6 of 6	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.*85delT		3_prime_UTR	Exon 7 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.*85delT		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.*85delT		3_prime_UTR	Exon 6 of 6	ENSP00000369820.3	P37287-1
	PIGA	ENST00000542278.6	TSL:5	c.*85delT		3_prime_UTR	Exon 6 of 6	ENSP00000442653.2	P37287-1
	PIGA	ENST00000634582.1	TSL:2	c.*85delT		3_prime_UTR	Exon 5 of 5	ENSP00000489540.1	P37287-3

Frequencies

GnomAD3 genomes AF: 0.00559 AC: 626 AN: 112033 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00228

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: 0.0000376

Gnomad OTH AF: 0.00199

GnomAD4 exome AF: 0.000650 AC: 491 AN: 755693 Hom.: 7 Cov.: 12 AF XY: 0.000557 AC XY: 113 AN XY: 202853

African (AFR) AF: 0.0234 AC: 424 AN: 18103

American (AMR) AF: 0.000841 AC: 19 AN: 22603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13526

East Asian (EAS) AF: 0.00 AC: 0 AN: 28357

South Asian (SAS) AF: 0.000108 AC: 4 AN: 37192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37383

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2194

European-Non Finnish (NFE) AF: 0.00000356 AC: 2 AN: 562339

Other (OTH) AF: 0.00124 AC: 42 AN: 33996

GnomAD4 genome AF: 0.00560 AC: 628 AN: 112085 Hom.: 9 Cov.: 22 AF XY: 0.00507 AC XY: 174 AN XY: 34293

African (AFR) AF: 0.0194 AC: 599 AN: 30866

American (AMR) AF: 0.00227 AC: 24 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53176

Other (OTH) AF: 0.00197 AC: 3 AN: 1526

Alfa AF: 0.00548 Hom.: 16

Bravo AF: 0.00668

Asia WGS AF: 0.000398 AC: 1 AN: 2522

ClinVar

ClinVar submissions as Germline

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		0.38
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: rs202201866; hg19: chrX-15339542;