rs61755362

Variant names:

• chr18-62161187-G-A
• rs61755362
• NM_176787.5:c.167C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_176787.5(PIGN):​c.167C>T​(p.Ala56Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,728 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.012 (178 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.94
• Publications: 7 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011676133).
• BP6: Variant 18-62161187-G-A is Benign according to our data. Variant chr18-62161187-G-A is described in ClinVar as Benign. ClinVar VariationId is 447939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1620/152288) while in subpopulation NFE AF = 0.0125 (847/68028). AF 95% confidence interval is 0.0118. There are 34 homozygotes in GnomAd4. There are 924 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.167C>T	p.Ala56Val	missense	Exon 4 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.167C>T	p.Ala56Val	missense	Exon 4 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.167C>T	p.Ala56Val	missense	Exon 3 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.167C>T	p.Ala56Val	missense	Exon 4 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.167C>T	p.Ala56Val	missense	Exon 3 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.167C>T		non_coding_transcript_exon	Exon 2 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1621 AN: 152170 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.0123 AC: 3073 AN: 249062 AF XY: 0.0125

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0534

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.0123 AC: 18007 AN: 1461440 Hom.: 178 Cov.: 30 AF XY: 0.0121 AC XY: 8792 AN XY: 727012

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00400 AC: 179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00342 AC: 295 AN: 86246

European-Finnish (FIN) AF: 0.0481 AC: 2566 AN: 53394

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14203 AN: 1111646

Other (OTH) AF: 0.00994 AC: 600 AN: 60364

GnomAD4 genome AF: 0.0106 AC: 1620 AN: 152288 Hom.: 34 Cov.: 33 AF XY: 0.0124 AC XY: 924 AN XY: 74468

African (AFR) AF: 0.00221 AC: 92 AN: 41566

American (AMR) AF: 0.00314 AC: 48 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.0558 AC: 592 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 847 AN: 68028

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0114 Hom.: 35

Bravo AF: 0.00692

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00278 AC: 11

ESP6500EA AF: 0.0127 AC: 106

ExAC AF: 0.0120 AC: 1449

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0130

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)
-	-	1	PIGN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.083	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.31
MPC		0.20
ClinPred		0.039	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.82
Mutation Taster		=95/5	polymorphism (auto)

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: rs61755362; hg19: chr18-59828420; COSMIC: COSV107433414; COSMIC: COSV107433414;