rs34231046

chr18-62045940-A-C

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.2712T>G(p.Phe904Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,384 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F904C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0083 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (145 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.753

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 (MetaRNN=0.005876571).
• BP6: Variant 18-62045940-A-C is Benign according to our data. Variant chr18-62045940-A-C is described in ClinVar as [Benign]. Clinvar id is 472226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62045940-A-C is described in Lovd as [Benign]. Variant chr18-62045940-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00831 (1266/152310) while in subpopulation NFE AF= 0.0144 (980/68020). AF 95% confidence interval is 0.0137. There are 6 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.2712T>G	p.Phe904Leu	missense_variant	31/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.2712T>G	p.Phe904Leu	missense_variant	31/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00937 AC: 2327 AN: 248306 Hom.: 14 AF XY: 0.00976 AC XY: 1315 AN XY: 134670

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00839

Gnomad FIN exome AF: 0.00553

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00861

GnomAD4 exome AF: 0.0122 AC: 17805 AN: 1461074 Hom.: 145 Cov.: 30 AF XY: 0.0120 AC XY: 8710 AN XY: 726762

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.00479

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00791

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.00935

GnomAD4 genome AF: 0.00831 AC: 1266 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74476

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0119 Hom.: 25

Bravo AF: 0.00822

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00222 AC: 9

ESP6500EA AF: 0.0127 AC: 107

ExAC AF: 0.00995 AC: 1203

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PIGN: BP4, BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.3
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0059	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Polyphen		0.024	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B
Vest4		0.27, 0.33
MutPred		0.15		Loss of MoRF binding (P = 0.4134);.;Loss of MoRF binding (P = 0.4134);Loss of MoRF binding (P = 0.4134);Loss of MoRF binding (P = 0.4134);.;.;.;.;.;Loss of MoRF binding (P = 0.4134);.;.;Loss of MoRF binding (P = 0.4134);.;Loss of MoRF binding (P = 0.4134);
MVP		0.31
MPC		0.026
ClinPred		0.036	T
GERP RS		0.22
Varity_R		0.21
gMVP		0.25

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: rs34231046; hg19: chr18-59713173;