rs9320000

Positions:

• chr18-62147035-G-A
• chr18-62147035-G-C
• chr18-62147035-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.741C>T​(p.His247His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,605,232 control chromosomes in the GnomAD database, including 308,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25655 hom., cov: 32)
  • Exomes 𝑓: 0.62 (282681 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.661

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-62147035-G-A is Benign according to our data. Variant chr18-62147035-G-A is described in ClinVar as [Benign]. Clinvar id is 403307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62147035-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.661 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.741C>T	p.His247His	synonymous_variant	9/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.741C>T	p.His247His	synonymous_variant	9/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.741C>T	p.His247His	synonymous_variant	8/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.741C>T		non_coding_transcript_exon_variant	7/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87016 AN: 151862 Hom.: 25635 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.583

GnomAD3 exomes AF: 0.622 AC: 153387 AN: 246620 Hom.: 48185 AF XY: 0.620 AC XY: 82970 AN XY: 133738

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.711

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.680

Gnomad SAS exome AF: 0.627

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.626

GnomAD4 exome AF: 0.621 AC: 902803 AN: 1453252 Hom.: 282681 Cov.: 43 AF XY: 0.621 AC XY: 449139 AN XY: 723088

Gnomad4 AFR exome AF: 0.418

Gnomad4 AMR exome AF: 0.711

Gnomad4 ASJ exome AF: 0.638

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.603

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.573 AC: 87075 AN: 151980 Hom.: 25655 Cov.: 32 AF XY: 0.575 AC XY: 42733 AN XY: 74274

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.617

Gnomad4 OTH AF: 0.583

Alfa AF: 0.596 Hom.: 13891

Bravo AF: 0.575

Asia WGS AF: 0.632 AC: 2190 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.31
DANN	Benign	0.41

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: rs9320000; hg19: chr18-59814268; COSMIC: COSV62952158;