rs753868318

Variant names:

• chr18-62140439-G-A
• rs753868318
• NM_176787.5:c.1004C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-62140439-G-A
• chr18-62140439-G-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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. P335P) has been classified as Likely benign.

• 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
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
• 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, 0.825

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.1004C>T	p.Pro335Leu	missense	Exon 12 of 31	NP_789744.1
	PIGN	NM_001438896.1		c.1004C>T	p.Pro335Leu	missense	Exon 12 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.1004C>T	p.Pro335Leu	missense	Exon 11 of 30	NP_036459.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.1004C>T	p.Pro335Leu	missense	Exon 12 of 31	ENSP00000492233.1
	PIGN	ENST00000400334.7	TSL:1	c.1004C>T	p.Pro335Leu	missense	Exon 11 of 30	ENSP00000383188.2
	PIGN	ENST00000638424.1	TSL:5	n.1004C>T		non_coding_transcript_exon	Exon 10 of 29	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

African (AFR) AF: 0.00 AC: 0 AN: 31940

American (AMR) AF: 0.00 AC: 0 AN: 40526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 38484

South Asian (SAS) AF: 0.00 AC: 0 AN: 79158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000662 AC: 7 AN: 1058096

Other (OTH) AF: 0.00 AC: 0 AN: 57754

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.53		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
Mutation Taster		=37/63	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: rs753868318; hg19: chr18-59807672;