rs1310594802

Variant names:

• chr18-62147004-T-C
• rs1310594802
• NM_176787.5:c.772A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_176787.5(PIGN):​c.772A>G​(p.Ile258Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.723
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_176787.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048663944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.772A>G	p.Ile258Val	missense	Exon 9 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.772A>G	p.Ile258Val	missense	Exon 9 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.772A>G	p.Ile258Val	missense	Exon 8 of 30	NP_036459.1	O95427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.772A>G	p.Ile258Val	missense	Exon 9 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.772A>G	p.Ile258Val	missense	Exon 8 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.772A>G		non_coding_transcript_exon	Exon 7 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248484 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460060 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726402

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110792

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.39
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.30	N
PhyloP100		0.72
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.48		Gain of catalytic residue at I258 (P = 0.0715)
MVP		0.33
MPC		0.023
ClinPred		0.038	T
GERP RS		-3.2
Varity_R		0.015
gMVP		0.33
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1310594802; hg19: chr18-59814237;