chrX-15335488-G-C

Variant names:

• chrX-15335488-G-C
• rs185874005
• NM_002641.4:c.-63+13C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002641.4(PIGA):​c.-63+13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 984,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 2 hem., cov: 25)
  • Exomes 𝑓: 0.0000057 (0 hom. 1 hem.)
• Consequence: PIGA NM_002641.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS2: High AC in GnomAd4 at 7 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.-63+13C>G		intron	N/A	NP_002632.1	P37287-1
	PIGA	NM_001440789.1		c.-63+13C>G		intron	N/A	NP_001427718.1
	PIGA	NM_001440790.1		c.13+13C>G		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.-63+13C>G		intron	N/A	ENSP00000369820.3	P37287-1
	PIGA	ENST00000482148.6	TSL:5	c.-63+13C>G		intron	N/A	ENSP00000489528.1	P37287-2
	PIGA	ENST00000634582.1	TSL:2	c.13+13C>G		intron	N/A	ENSP00000489540.1	P37287-3

Frequencies

GnomAD3 genomes AF: 0.0000618 AC: 7 AN: 113296 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000574 AC: 5 AN: 871289 Hom.: 0 Cov.: 28 AF XY: 0.00000373 AC XY: 1 AN XY: 268091

African (AFR) AF: 0.000107 AC: 2 AN: 18712

American (AMR) AF: 0.00 AC: 0 AN: 8417

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12061

East Asian (EAS) AF: 0.00 AC: 0 AN: 20711

South Asian (SAS) AF: 0.00 AC: 0 AN: 24462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19625

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3444

European-Non Finnish (NFE) AF: 0.00000412 AC: 3 AN: 728033

Other (OTH) AF: 0.00 AC: 0 AN: 35824

GnomAD4 genome AF: 0.0000618 AC: 7 AN: 113296 Hom.: 0 Cov.: 25 AF XY: 0.0000564 AC XY: 2 AN XY: 35438

African (AFR) AF: 0.000192 AC: 6 AN: 31224

American (AMR) AF: 0.00 AC: 0 AN: 10888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2817

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53376

Other (OTH) AF: 0.00 AC: 0 AN: 1532

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.40
PhyloP100		2.0
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs185874005; hg19: chrX-15353610;