rs587777398

Positions:

• chrX-15331701-C-A
• chrX-15331701-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002641.4(PIGA):​c.230G>T​(p.Arg77Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PIGA NM_002641.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.49

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-15331701-C-A is Pathogenic according to our data. Variant chrX-15331701-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 132816.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-15331701-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGA	NM_002641.4	c.230G>T	p.Arg77Leu	missense_variant	2/6	ENST00000333590.6	NP_002632.1
PIGA	NM_020473.3	c.13+3800G>T		intron_variant			NP_065206.3
PIGA	NR_033835.1	n.346G>T		non_coding_transcript_exon_variant	2/6
PIGA	NR_033836.1	n.173+173G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGA	ENST00000333590.6	c.230G>T	p.Arg77Leu	missense_variant	2/6	1	NM_002641.4	ENSP00000369820	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.1	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	D;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.84		Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);Loss of MoRF binding (P = 0.0165);
MVP		0.85
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.91

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: rs587777398; hg19: chrX-15349823;