rs1555694236

Variant names:

• chr18-62146025-C-A
• rs1555694236
• NM_176787.5:c.806G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_176787.5(PIGN):​c.806G>T​(p.Gly269Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000793 in 1,261,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96
• 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: Likely_pathogenic. The variant received 8 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, 4 uncertain in NM_176787.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

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.806G>T	p.Gly269Val	missense splice_region	Exon 10 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.806G>T	p.Gly269Val	missense splice_region	Exon 10 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.806G>T	p.Gly269Val	missense splice_region	Exon 9 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.806G>T	p.Gly269Val	missense splice_region	Exon 10 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.806G>T	p.Gly269Val	missense splice_region	Exon 9 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.806G>T		splice_region non_coding_transcript_exon	Exon 8 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1261642 Hom.: 0 Cov.: 18 AF XY: 0.00000158 AC XY: 1 AN XY: 634104

African (AFR) AF: 0.00 AC: 0 AN: 28172

American (AMR) AF: 0.00 AC: 0 AN: 34660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23048

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 953048

Other (OTH) AF: 0.00 AC: 0 AN: 53112

GnomAD4 genome Cov.: 32

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.83		Loss of disorder (P = 0.0318)
MVP		0.85
MPC		0.21
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs1555694236; hg19: chr18-59813258; COSMIC: COSV108197604; COSMIC: COSV108197604;