rs753868318

Positions:

• chr18-62140439-G-A
• chr18-62140439-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_176787.5(PIGN):​c.1004C>T​(p.Pro335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000504 in 1,388,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1004C>T	p.Pro335Leu	missense_variant	12/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1004C>T	p.Pro335Leu	missense_variant	12/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1004C>T	p.Pro335Leu	missense_variant	11/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1004C>T		non_coding_transcript_exon_variant	10/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000504 AC: 7 AN: 1388454 Hom.: 0 Cov.: 22 AF XY: 0.00000870 AC XY: 6 AN XY: 689858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000662

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 335 of the PIGN protein (p.Pro335Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 472204). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T;T;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;.;D;.;D;.;D;.;D;D;D;D;.;.;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;.;.;M;.;M;.;M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.017	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.015	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.96, 0.96
MutPred		0.53		Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);.;Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);Gain of catalytic residue at P335 (P = 0.1328);
MVP		0.78
MPC		0.20
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs753868318; hg19: chr18-59807672;