NM_176787.5:c.309T>C

Variant names:

• chr18-62157721-A-G
• rs17069511
• NM_176787.5:c.309T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_176787.5(PIGN):​c.309T>C​(p.Ala103Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,612,106 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (122 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.570
• 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: 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 18-62157721-A-G is Benign according to our data. Variant chr18-62157721-A-G is described in ClinVar as Benign. ClinVar VariationId is 472230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.57 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0616 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.309T>C	p.Ala103Ala	synonymous	Exon 5 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.309T>C	p.Ala103Ala	synonymous	Exon 5 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.309T>C	p.Ala103Ala	synonymous	Exon 4 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.309T>C	p.Ala103Ala	synonymous	Exon 5 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.309T>C	p.Ala103Ala	synonymous	Exon 4 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.309T>C		non_coding_transcript_exon	Exon 3 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152226 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.0105 AC: 2589 AN: 245868 AF XY: 0.00788

Gnomad AFR exome AF: 0.000592

Gnomad AMR exome AF: 0.0683

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00232 AC: 3392 AN: 1459762 Hom.: 122 Cov.: 30 AF XY: 0.00193 AC XY: 1400 AN XY: 725942

African (AFR) AF: 0.000419 AC: 14 AN: 33452

American (AMR) AF: 0.0636 AC: 2825 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.0111 AC: 439 AN: 39662

South Asian (SAS) AF: 0.0000583 AC: 5 AN: 85730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110968

Other (OTH) AF: 0.00143 AC: 86 AN: 60312

GnomAD4 genome AF: 0.00375 AC: 572 AN: 152344 Hom.: 14 Cov.: 33 AF XY: 0.00416 AC XY: 310 AN XY: 74510

African (AFR) AF: 0.000793 AC: 33 AN: 41588

American (AMR) AF: 0.0310 AC: 475 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00400 Hom.: 8

Bravo AF: 0.00697

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.75
PhyloP100		0.57
Mutation Taster		=86/14	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: rs17069511; hg19: chr18-59824954;