rs9320001

Variant names:

• chr18-62147091-G-C
• rs9320001
• NM_176787.5:c.685C>G

Your query was ambiguous. Multiple possible variants found:

• chr18-62147091-G-C
• chr18-62147091-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176787.5(PIGN):​c.685C>G​(p.His229Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,587,026 control chromosomes in the GnomAD database, including 468,501 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. H229R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.80 (48759 hom., cov: 32)
  • Exomes 𝑓: 0.76 (419742 hom.)
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.89
• Publications: 37 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.619225E-7).
• BP6: Variant 18-62147091-G-C is Benign according to our data. Variant chr18-62147091-G-C is described in ClinVar as Benign. ClinVar VariationId is 403308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

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.685C>G	p.His229Asp	missense	Exon 9 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.685C>G	p.His229Asp	missense	Exon 9 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.685C>G	p.His229Asp	missense	Exon 8 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.685C>G	p.His229Asp	missense	Exon 9 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.685C>G	p.His229Asp	missense	Exon 8 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.685C>G		non_coding_transcript_exon	Exon 7 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121287 AN: 152032 Hom.: 48693 Cov.: 32

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.792

GnomAD2 exomes AF: 0.788 AC: 190899 AN: 242216 AF XY: 0.786

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.819

Gnomad EAS exome AF: 0.912

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.762 AC: 1093869 AN: 1434876 Hom.: 419742 Cov.: 38 AF XY: 0.764 AC XY: 545741 AN XY: 714358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.877 AC: 29071 AN: 33166

American (AMR) AF: 0.826 AC: 36294 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 21129 AN: 25810

East Asian (EAS) AF: 0.879 AC: 34565 AN: 39330

South Asian (SAS) AF: 0.845 AC: 72013 AN: 85222

European-Finnish (FIN) AF: 0.744 AC: 39490 AN: 53056

Middle Eastern (MID) AF: 0.838 AC: 4786 AN: 5714

European-Non Finnish (NFE) AF: 0.744 AC: 809995 AN: 1089248

Other (OTH) AF: 0.784 AC: 46526 AN: 59378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.798 AC: 121409 AN: 152150 Hom.: 48759 Cov.: 32 AF XY: 0.799 AC XY: 59445 AN XY: 74370

African (AFR) AF: 0.873 AC: 36287 AN: 41548

American (AMR) AF: 0.814 AC: 12445 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2835 AN: 3472

East Asian (EAS) AF: 0.908 AC: 4712 AN: 5188

South Asian (SAS) AF: 0.852 AC: 4109 AN: 4822

European-Finnish (FIN) AF: 0.753 AC: 7946 AN: 10554

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50515 AN: 67970

Other (OTH) AF: 0.792 AC: 1672 AN: 2110

Alfa AF: 0.763 Hom.: 14479

Bravo AF: 0.806

TwinsUK AF: 0.742 AC: 2753

ALSPAC AF: 0.745 AC: 2870

ESP6500AA AF: 0.878 AC: 3151

ESP6500EA AF: 0.753 AC: 6121

ExAC AF: 0.782 AC: 94288

Asia WGS AF: 0.864 AC: 2992 AN: 3460

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
PhyloP100		1.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.027
ClinPred		0.00068	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.35
Mutation Taster		=98/2	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: rs9320001; hg19: chr18-59814324; COSMIC: COSV62951859;