rs375371562

Variant names:

• chrX-15326056-T-C
• rs375371562
• NM_002641.4:c.716-10A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002641.4(PIGA):​c.716-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,080,375 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 32 hem.)
• Consequence: PIGA NM_002641.4 intron
• Scores: Splicing: ADA: 0.0001122
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.356
• 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):

• multiple congenital anomalies-hypotonia-seizures syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-15326056-T-C is Benign according to our data. Variant chrX-15326056-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 388213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 17 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	NM_002641.4	MANE Select	c.716-10A>G		intron	N/A	NP_002632.1
	PIGA	NM_001440789.1		c.809-10A>G		intron	N/A	NP_001427718.1
	PIGA	NM_001440790.1		c.107-10A>G		intron	N/A	NP_001427719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.716-10A>G		intron	N/A	ENSP00000369820.3
	PIGA	ENST00000635480.1	TSL:3	n.328A>G		non_coding_transcript_exon	Exon 1 of 3
	PIGA	ENST00000542278.6	TSL:5	c.716-10A>G		intron	N/A	ENSP00000442653.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 17 AN: 112322 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000107 AC: 16 AN: 148852 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.000726

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000849

Gnomad OTH exome AF: 0.000294

GnomAD4 exome AF: 0.000118 AC: 114 AN: 968053 Hom.: 0 Cov.: 16 AF XY: 0.000120 AC XY: 32 AN XY: 266087

African (AFR) AF: 0.0000437 AC: 1 AN: 22899

American (AMR) AF: 0.000141 AC: 4 AN: 28359

Ashkenazi Jewish (ASJ) AF: 0.000408 AC: 7 AN: 17157

East Asian (EAS) AF: 0.00 AC: 0 AN: 28594

South Asian (SAS) AF: 0.00 AC: 0 AN: 44518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39471

Middle Eastern (MID) AF: 0.00214 AC: 8 AN: 3738

European-Non Finnish (NFE) AF: 0.000116 AC: 86 AN: 741927

Other (OTH) AF: 0.000193 AC: 8 AN: 41390

GnomAD4 genome AF: 0.000151 AC: 17 AN: 112322 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34464

African (AFR) AF: 0.00 AC: 0 AN: 30926

American (AMR) AF: 0.000852 AC: 9 AN: 10563

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3629

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6093

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53284

Other (OTH) AF: 0.000661 AC: 1 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000219

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.10
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: rs375371562; hg19: chrX-15344178;