rs61751426

chrX-15331406-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002641.4(PIGA):c.525T>C(p.Leu175=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,209,482 control chromosomes in the GnomAD database, including 6 homozygotes. There are 210 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 0.00036 (0 hom., 16 hem., cov: 24)
  • Exomes 𝑓: 0.00056 (6 hom. 194 hem.)
• Consequence: PIGA NM_002641.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.207

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-15331406-A-G is Benign according to our data. Variant chrX-15331406-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 471952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.207 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000561 (615/1097122) while in subpopulation EAS AF= 0.0196 (593/30201). AF 95% confidence interval is 0.0183. There are 6 homozygotes in gnomad4_exome. There are 194 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGA	NM_002641.4	c.525T>C	p.Leu175=	synonymous_variant	2/6	ENST00000333590.6
PIGA	NM_020473.3	c.13+4095T>C		intron_variant
PIGA	NR_033835.1	n.457+184T>C		intron_variant, non_coding_transcript_variant
PIGA	NR_033836.1	n.173+468T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGA	ENST00000333590.6	c.525T>C	p.Leu175=	synonymous_variant	2/6	1	NM_002641.4	P1

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 40 AN: 112305 Hom.: 0 Cov.: 24 AF XY: 0.000464 AC XY: 16 AN XY: 34467

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000941

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00100 AC: 184 AN: 183454 Hom.: 1 AF XY: 0.000869 AC XY: 59 AN XY: 67894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000561 AC: 615 AN: 1097122 Hom.: 6 Cov.: 29 AF XY: 0.000535 AC XY: 194 AN XY: 362486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0196

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.000356 AC: 40 AN: 112360 Hom.: 0 Cov.: 24 AF XY: 0.000463 AC XY: 16 AN XY: 34532

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000940

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0109

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000559

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2017

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Multiple congenital anomalies-hypotonia-seizures syndrome 2;C3806670:Paroxysmal nocturnal hemoglobinuria 1;CN307964:Neurodevelopmental disorder with epilepsy and hemochromatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.5
Dann	Benign	0.80

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: rs61751426; hg19: chrX-15349528; COSMIC: COSV100363367; COSMIC: COSV100363367;