rs17714063

Positions:

• chr18-62101142-A-G
• chr18-62101142-A-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.2010T>C​(p.Thr670Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,606,734 control chromosomes in the GnomAD database, including 42,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2942 hom., cov: 32)
  • Exomes 𝑓: 0.22 (40034 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0560

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=-0.61).
• BP6: Variant 18-62101142-A-G is Benign according to our data. Variant chr18-62101142-A-G is described in ClinVar as [Benign]. Clinvar id is 403300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.056 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.2010T>C	p.Thr670Thr	synonymous_variant	22/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2010T>C	p.Thr670Thr	synonymous_variant	22/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2010T>C	p.Thr670Thr	synonymous_variant	21/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.2010T>C		non_coding_transcript_exon_variant	20/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25948 AN: 152082 Hom.: 2941 Cov.: 32

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.178 AC: 43967 AN: 247562 Hom.: 4855 AF XY: 0.181 AC XY: 24327 AN XY: 134386

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.00279

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.224 AC: 326540 AN: 1454534 Hom.: 40034 Cov.: 30 AF XY: 0.223 AC XY: 161168 AN XY: 724040

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.00141

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.171 AC: 25954 AN: 152200 Hom.: 2942 Cov.: 32 AF XY: 0.168 AC XY: 12469 AN XY: 74404

Gnomad4 AFR AF: 0.0496

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: 0.195

Alfa AF: 0.229 Hom.: 1732

Bravo AF: 0.159

Asia WGS AF: 0.0810 AC: 284 AN: 3478

EpiCase AF: 0.252

EpiControl AF: 0.252

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

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	-0.61
CADD	Benign	6.4
DANN	Benign	0.75

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: rs17714063; hg19: chr18-59768375;