rs200658159

Positions:

• chr18-62090521-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_176787.5(PIGN):​c.2238A>G​(p.Ile746Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,611,218 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I746R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.108

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 -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-62090522-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 659307.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006445229).
• BP6: Variant 18-62090521-T-C is Benign according to our data. Variant chr18-62090521-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 539565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62090521-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.2238A>G	p.Ile746Met	missense_variant	24/31	ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.2238A>G	p.Ile746Met	missense_variant	24/31	1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00135 AC: 333 AN: 247046 Hom.: 0 AF XY: 0.00144 AC XY: 193 AN XY: 134068

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000294

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00120 AC: 1754 AN: 1458906 Hom.: 5 Cov.: 28 AF XY: 0.00124 AC XY: 901 AN XY: 725768

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74480

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00200 Hom.: 3

Bravo AF: 0.00131

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000827 AC: 3

ESP6500EA AF: 0.00282 AC: 23

ExAC AF: 0.00123 AC: 149

EpiCase AF: 0.00192

EpiControl AF: 0.00190

ClinVar

Significance: Benign/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	GeneDx	Feb 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2018

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.013	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N;.;N;N;N;.;.;.;.;.;N;.;.;N;.;N;.;.
MutationTaster	Benign	0.87	D;D
PrimateAI	Benign	0.28	T
Polyphen		0.0020	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.
Vest4		0.23
MVP		0.51
MPC		0.024
ClinPred		0.0041	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.22

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: rs200658159; hg19: chr18-59757754;