X-15331839-C-A

Variant names:

• chrX-15331839-C-A
• NM_002641.4:c.92G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002641.4(PIGA):​c.92G>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,085 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.46

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10020551).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGA	NM_002641.4	c.92G>T	p.Arg31Leu	missense_variant	Exon 2 of 6	ENST00000333590.6	NP_002632.1
PIGA	NM_020473.3	c.13+3662G>T		intron_variant	Intron 1 of 4		NP_065206.3
PIGA	NR_033835.1	n.208G>T		non_coding_transcript_exon_variant	Exon 2 of 6
PIGA	NR_033836.1	n.173+35G>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6	c.92G>T	p.Arg31Leu	missense_variant	Exon 2 of 6	1	NM_002641.4	ENSP00000369820.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098085 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 2 AN XY: 363441

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000594

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0060
DANN	Benign	0.74
DEOGEN2	Benign	0.16	T;T;.;.
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.70	.;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.53	N;.;.;.
REVEL	Benign	0.086
Sift	Benign	0.058	T;.;.;.
Sift4G	Benign	0.076	T;T;T;.
Polyphen		0.014	B;B;B;.
Vest4		0.11
MutPred		0.59		Loss of MoRF binding (P = 0.0685);Loss of MoRF binding (P = 0.0685);Loss of MoRF binding (P = 0.0685);Loss of MoRF binding (P = 0.0685);
MVP		0.22
MPC		0.70
ClinPred		0.21	T
GERP RS		-11
Varity_R		0.049
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15349961;