rs1555944375

Variant names:

• chrX-15324758-T-C
• rs1555944375
• NM_002641.4:c.1095A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_002641.4(PIGA):​c.1095A>G​(p.Gln365Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: PIGA NM_002641.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.792
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-15324758-T-C is Benign according to our data. Variant chrX-15324758-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 539325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.792 with no splicing effect.

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.1095A>G	p.Gln365Gln	synonymous	Exon 5 of 6	NP_002632.1
	PIGA	NM_001440789.1		c.1188A>G	p.Gln396Gln	synonymous	Exon 6 of 7	NP_001427718.1
	PIGA	NM_001440790.1		c.486A>G	p.Gln162Gln	synonymous	Exon 5 of 6	NP_001427719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGA	ENST00000333590.6	TSL:1 MANE Select	c.1095A>G	p.Gln365Gln	synonymous	Exon 5 of 6	ENSP00000369820.3
	PIGA	ENST00000475746.1	TSL:1	c.81+262A>G		intron	N/A	ENSP00000488970.1
	PIGA	ENST00000542278.6	TSL:5	c.1095A>G	p.Gln365Gln	synonymous	Exon 5 of 6	ENSP00000442653.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1093806 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359280

African (AFR) AF: 0.00 AC: 0 AN: 26312

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838146

Other (OTH) AF: 0.0000218 AC: 1 AN: 45938

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 2 Benign:1

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.95
DANN	Benign	0.32
PhyloP100		0.79
PromoterAI		0.0092	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1555944375; hg19: chrX-15342880;