18-62084547-G-T

Variant names:

• chr18-62084547-G-T
• rs375027313
• NM_176787.5:c.2486C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_176787.5(PIGN):​c.2486C>A​(p.Ala829Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,399,054 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. A829V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.2486C>A	p.Ala829Asp	missense_variant	Exon 27 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.2486C>A	p.Ala829Asp	missense_variant	Exon 27 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.2486C>A	p.Ala829Asp	missense_variant	Exon 26 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.*454C>A		non_coding_transcript_exon_variant	Exon 25 of 29	5		ENSP00000491963.1
PIGN	ENST00000638424.1	n.*454C>A		3_prime_UTR_variant	Exon 25 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399054 Hom.: 0 Cov.: 27 AF XY: 0.00000434 AC XY: 3 AN XY: 691220

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 36704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 36428

South Asian (SAS) AF: 0.00 AC: 0 AN: 78872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1076294

Other (OTH) AF: 0.00 AC: 0 AN: 58178

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.0	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.
PhyloP100		4.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.017	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Polyphen		0.27	B;.;B;B;B;.;.;.;.;.;B;.;.;B;.;B;.;.
Vest4		0.89
MutPred		0.89		Gain of ubiquitination at K834 (P = 0.1047);.;Gain of ubiquitination at K834 (P = 0.1047);Gain of ubiquitination at K834 (P = 0.1047);Gain of ubiquitination at K834 (P = 0.1047);.;.;Gain of ubiquitination at K834 (P = 0.1047);.;.;Gain of ubiquitination at K834 (P = 0.1047);Gain of ubiquitination at K834 (P = 0.1047);.;Gain of ubiquitination at K834 (P = 0.1047);.;Gain of ubiquitination at K834 (P = 0.1047);Gain of ubiquitination at K834 (P = 0.1047);Gain of ubiquitination at K834 (P = 0.1047);
MVP		0.91
MPC		0.068
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.76
Mutation Taster		=60/40	polymorphism

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: rs375027313; hg19: chr18-59751780;