18-62113191-A-G

Position:

• chr18-62113191-A-G

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.1377T>C​(p.Ser459Ser) 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 1,610,870 control chromosomes in the GnomAD database, including 43,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2930 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40134 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.789

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=-0.5).
• BP6: Variant 18-62113191-A-G is Benign according to our data. Variant chr18-62113191-A-G is described in ClinVar as [Benign]. Clinvar id is 403303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62113191-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.789 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.1377T>C	p.Ser459Ser	synonymous_variant	16/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1377T>C	p.Ser459Ser	synonymous_variant	16/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1377T>C	p.Ser459Ser	synonymous_variant	15/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1377T>C		non_coding_transcript_exon_variant	14/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25712 AN: 152060 Hom.: 2929 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: 0.00500

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.177 AC: 43791 AN: 246832 Hom.: 4798 AF XY: 0.181 AC XY: 24222 AN XY: 133870

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.00281

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.225 AC: 328421 AN: 1458692 Hom.: 40134 Cov.: 32 AF XY: 0.223 AC XY: 161916 AN XY: 725620

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.00142

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.169 AC: 25717 AN: 152178 Hom.: 2930 Cov.: 32 AF XY: 0.166 AC XY: 12381 AN XY: 74390

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.194

Alfa AF: 0.226 Hom.: 4931

Bravo AF: 0.157

Asia WGS AF: 0.0810 AC: 283 AN: 3474

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	-0.50
CADD	Benign	5.3
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17714875; hg19: chr18-59780424; COSMIC: COSV62950788; COSMIC: COSV62950788;