rs185874005

chrX-15335488-G-AchrX-15335488-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002641.4(PIGA):c.-63+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 984,625 control chromosomes in the GnomAD database, including 15 homozygotes. There are 336 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., 194 hem., cov: 25)
  • Exomes 𝑓: 0.00060 (6 hom. 142 hem.)
• Consequence: PIGA NM_002641.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-15335488-G-A is Benign according to our data. Variant chrX-15335488-G-A is described in ClinVar as [Benign]. Clinvar id is 382688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00574 (651/113344) while in subpopulation AFR AF= 0.0198 (618/31288). AF 95% confidence interval is 0.0185. There are 9 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.-63+13C>T		intron_variant		ENST00000333590.6
PIGA	NM_020473.3	c.13+13C>T		intron_variant
PIGA	NR_033835.1	n.54+13C>T		intron_variant, non_coding_transcript_variant
PIGA	NR_033836.1	n.54+13C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.-63+13C>T		intron_variant		1	NM_002641.4	P1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 649 AN: 113293 Hom.: 9 Cov.: 25 AF XY: 0.00547 AC XY: 194 AN XY: 35437

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00239

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.000355

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000768 AC: 5 AN: 6514 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 420

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000773

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000601 AC: 524 AN: 871281 Hom.: 6 Cov.: 28 AF XY: 0.000530 AC XY: 142 AN XY: 268083

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.000950

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000687

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00574 AC: 651 AN: 113344 Hom.: 9 Cov.: 25 AF XY: 0.00547 AC XY: 194 AN XY: 35498

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00239

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.000356

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00193

Bravo AF: 0.00669

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.1
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs185874005; hg19: chrX-15353610;