rs34227891

Variant names:

• chr18-62143330-A-G
• rs34227891
• NM_176787.5:c.939T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.939T>C​(p.Asn313Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,507,966 control chromosomes in the GnomAD database, including 48,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4536 hom., cov: 32)
  • Exomes 𝑓: 0.25 (44171 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.238
• Publications: 14 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-62143330-A-G is Benign according to our data. Variant chr18-62143330-A-G is described in ClinVar as Benign. ClinVar VariationId is 403305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.238 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGN	NM_176787.5	c.939T>C	p.Asn313Asn	synonymous_variant	Exon 11 of 31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.939T>C	p.Asn313Asn	synonymous_variant	Exon 11 of 31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.939T>C	p.Asn313Asn	synonymous_variant	Exon 10 of 30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.939T>C		non_coding_transcript_exon_variant	Exon 9 of 29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36106 AN: 151884 Hom.: 4533 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.192 AC: 38197 AN: 198452 AF XY: 0.191

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0681

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.247 AC: 334767 AN: 1355964 Hom.: 44171 Cov.: 23 AF XY: 0.245 AC XY: 165284 AN XY: 674710

African (AFR) AF: 0.199 AC: 6207 AN: 31196

American (AMR) AF: 0.130 AC: 5257 AN: 40368

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6648 AN: 24948

East Asian (EAS) AF: 0.0682 AC: 2599 AN: 38108

South Asian (SAS) AF: 0.141 AC: 11246 AN: 79906

European-Finnish (FIN) AF: 0.251 AC: 12829 AN: 51066

Middle Eastern (MID) AF: 0.315 AC: 1743 AN: 5526

European-Non Finnish (NFE) AF: 0.267 AC: 274625 AN: 1028258

Other (OTH) AF: 0.241 AC: 13613 AN: 56588

GnomAD4 genome AF: 0.238 AC: 36132 AN: 152002 Hom.: 4536 Cov.: 32 AF XY: 0.233 AC XY: 17299 AN XY: 74300

African (AFR) AF: 0.211 AC: 8753 AN: 41462

American (AMR) AF: 0.196 AC: 3002 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 950 AN: 3470

East Asian (EAS) AF: 0.0784 AC: 406 AN: 5180

South Asian (SAS) AF: 0.144 AC: 694 AN: 4822

European-Finnish (FIN) AF: 0.263 AC: 2771 AN: 10548

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18673 AN: 67920

Other (OTH) AF: 0.258 AC: 545 AN: 2116

Alfa AF: 0.260 Hom.: 4145

Bravo AF: 0.233

Asia WGS AF: 0.132 AC: 458 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Inborn genetic diseases Benign:1

Mar 19, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.8
DANN	Benign	0.62
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs34227891; hg19: chr18-59810563; COSMIC: COSV62949022; COSMIC: COSV62949022;