18-62084586-T-G

Variant names:

• chr18-62084586-T-G
• rs200750917
• NM_176787.5:c.2447A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_176787.5(PIGN):​c.2447A>C​(p.Tyr816Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,404,884 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y816C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

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.2447A>C	p.Tyr816Ser	missense	Exon 27 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2447A>C	p.Tyr816Ser	missense	Exon 27 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2447A>C	p.Tyr816Ser	missense	Exon 26 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.2447A>C	p.Tyr816Ser	missense	Exon 27 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2447A>C	p.Tyr816Ser	missense	Exon 26 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.*415A>C		non_coding_transcript_exon	Exon 25 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404884 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 693996

African (AFR) AF: 0.00 AC: 0 AN: 31838

American (AMR) AF: 0.00 AC: 0 AN: 36988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 36600

South Asian (SAS) AF: 0.00 AC: 0 AN: 79500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080432

Other (OTH) AF: 0.00 AC: 0 AN: 58372

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	Benign	0.17
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.39
Sift	Benign	0.26	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.94
MutPred		0.77		Gain of helix (P = 0.132)
MVP		0.84
MPC		0.21
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.55
gMVP		0.72
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200750917; hg19: chr18-59751819;