rs376615257

chr18-62154635-G-Achr18-62154635-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_176787.5(PIGN):c.459C>T(p.His153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,540,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.15

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 -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 18-62154635-G-A is Benign according to our data. Variant chr18-62154635-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000395 (60/151972) while in subpopulation AFR AF= 0.00138 (57/41368). AF 95% confidence interval is 0.00109. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.459C>T	p.His153=	synonymous_variant	7/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.459C>T	p.His153=	synonymous_variant	7/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151972 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000184 AC: 45 AN: 244936 Hom.: 0 AF XY: 0.000158 AC XY: 21 AN XY: 132948

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.000178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000627 AC: 87 AN: 1388054 Hom.: 0 Cov.: 22 AF XY: 0.0000619 AC XY: 43 AN XY: 694430

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.000340

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000478

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000114

Gnomad4 OTH exome AF: 0.0000692

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151972 Hom.: 0 Cov.: 33 AF XY: 0.000431 AC XY: 32 AN XY: 74214

Gnomad4 AFR AF: 0.00138

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.000525

EpiCase AF: 0.0000547

EpiControl AF: 0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PIGN: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.2
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs376615257; hg19: chr18-59821868;