rs747229315

Variant names:

• chr18-62138303-G-A
• rs747229315
• NM_176787.5:c.1117-5C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_176787.5(PIGN):​c.1117-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,536,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: PIGN NM_176787.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.67
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-62138303-G-A is Benign according to our data. Variant chr18-62138303-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1117-5C>T		splice_region intron	N/A	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.1117-5C>T		splice_region intron	N/A	NP_001425825.1
	PIGN	NM_012327.6		c.1117-5C>T		splice_region intron	N/A	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.1117-5C>T		splice_region intron	N/A	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.1117-5C>T		splice_region intron	N/A	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.1117-5C>T		splice_region intron	N/A	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000237 AC: 35 AN: 147382 AF XY: 0.000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000325 AC: 45 AN: 1383960 Hom.: 0 Cov.: 30 AF XY: 0.0000337 AC XY: 23 AN XY: 682128

African (AFR) AF: 0.00 AC: 0 AN: 30900

American (AMR) AF: 0.00130 AC: 43 AN: 33202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35388

South Asian (SAS) AF: 0.00 AC: 0 AN: 75478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071638

Other (OTH) AF: 0.0000348 AC: 2 AN: 57514

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000147

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.50
PhyloP100		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs747229315; hg19: chr18-59805536;