rs9319997

Positions:

• chr18-62106804-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.1752G>A​(p.Leu584=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,603,330 control chromosomes in the GnomAD database, including 42,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2934 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39818 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.250

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 18-62106804-C-T is Benign according to our data. Variant chr18-62106804-C-T is described in ClinVar as [Benign]. Clinvar id is 403302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62106804-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1752G>A	p.Leu584=	synonymous_variant	19/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1752G>A	p.Leu584=	synonymous_variant	19/31	1	NM_176787.5	ENSP00000492233	P1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25729 AN: 152074 Hom.: 2933 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.173 AC: 40731 AN: 234998 Hom.: 4338 AF XY: 0.176 AC XY: 22402 AN XY: 127074

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.225 AC: 326239 AN: 1451138 Hom.: 39818 Cov.: 31 AF XY: 0.223 AC XY: 160565 AN XY: 720926

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.00140

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.169 AC: 25734 AN: 152192 Hom.: 2934 Cov.: 32 AF XY: 0.167 AC XY: 12390 AN XY: 74398

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.194

Alfa AF: 0.229 Hom.: 5758

Bravo AF: 0.157

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

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 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.2
DANN	Benign	0.59

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: rs9319997; hg19: chr18-59774037; COSMIC: COSV62952142; COSMIC: COSV62952142;