18-62147021-T-A

Variant names:

• chr18-62147021-T-A
• rs886039216
• NM_176787.5:c.755A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_176787.5(PIGN):​c.755A>T​(p.Asp252Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.43
• Publications: 5 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-62147021-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1012442.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 18-62147021-T-A is Pathogenic according to our data. Variant chr18-62147021-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 264634.Status of the report is no_assertion_criteria_provided, 0 stars.

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.755A>T	p.Asp252Val	missense	Exon 9 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.755A>T	p.Asp252Val	missense	Exon 9 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.755A>T	p.Asp252Val	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.755A>T	p.Asp252Val	missense	Exon 9 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.755A>T	p.Asp252Val	missense	Exon 8 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.755A>T		non_coding_transcript_exon	Exon 7 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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	0.81
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.4
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.57		Loss of solvent accessibility (P = 0.0544)
MVP		0.92
MPC		0.22
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs886039216; hg19: chr18-59814254;