chr18-62140439-G-C

Variant names:

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

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>G​(p.Pro335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P335L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Not reported in ClinVar
• 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, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.1004C>G	p.Pro335Arg	missense_variant	Exon 12 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.1004C>G	p.Pro335Arg	missense_variant	Exon 12 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.1004C>G	p.Pro335Arg	missense_variant	Exon 11 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.1004C>G		non_coding_transcript_exon_variant	Exon 10 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000486 AC: 1 AN: 205826 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388454 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 689858

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

American (AMR) AF: 0.0000247 AC: 1 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: 0.00 AC: 0 AN: 1058096

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;.;.;.;T;.;T;.;T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;.;D;.;D;.;D;D;D;D;.;.;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;.;.;M;.;M;.;M;.;.;.;.;.;.;.
PhyloP100		8.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.021	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.027	.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.56		Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);.;Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);Gain of methylation at P335 (P = 0.0601);
MVP		0.75
MPC		0.20
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.52
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;