rs147306123

Positions:

• chr18-62107043-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_176787.5(PIGN):​c.1617T>C​(p.Tyr539=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,590,276 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.446

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 18-62107043-A-G is Benign according to our data. Variant chr18-62107043-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 472208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00265 (404/152306) while in subpopulation NFE AF= 0.00432 (294/68014). AF 95% confidence interval is 0.00392. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.1617T>C	p.Tyr539=	synonymous_variant	18/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.1617T>C	p.Tyr539=	synonymous_variant	18/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 404 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00281 AC: 600 AN: 213260 Hom.: 1 AF XY: 0.00272 AC XY: 310 AN XY: 114174

Gnomad AFR exome AF: 0.000733

Gnomad AMR exome AF: 0.000546

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000155

Gnomad FIN exome AF: 0.00267

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00402 AC: 5777 AN: 1437970 Hom.: 14 Cov.: 29 AF XY: 0.00386 AC XY: 2750 AN XY: 712726

Gnomad4 AFR exome AF: 0.000700

Gnomad4 AMR exome AF: 0.000525

Gnomad4 ASJ exome AF: 0.000157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000978

Gnomad4 FIN exome AF: 0.00297

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00432

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00356 Hom.: 1

Bravo AF: 0.00245

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PIGN: BP4, BP7 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2016

This alteration is classified as likely 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

- -

PIGN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.2
DANN	Benign	0.35

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: rs147306123; hg19: chr18-59774276; COSMIC: COSV100716362; COSMIC: COSV100716362;