18-62074825-GA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_176787.5(PIGN):c.2577-5_2577-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,565,040 control chromosomes in the GnomAD database, including 215 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (174 hom.)
• Consequence: PIGN NM_176787.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0730

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 18-62074825-G-GA is Benign according to our data. Variant chr18-62074825-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 472221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGN	NM_176787.5	c.2577-5_2577-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000640252.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGN	ENST00000640252.2	c.2577-5_2577-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_176787.5	P1

Frequencies

GnomAD3 genomes AF: 0.00978 AC: 1467 AN: 150064 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000862

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0698

Gnomad SAS AF: 0.00673

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00828

GnomAD3 exomes AF: 0.0141 AC: 2956 AN: 208964 Hom.: 53 AF XY: 0.0140 AC XY: 1579 AN XY: 113160

Gnomad AFR exome AF: 0.00372

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00419

Gnomad EAS exome AF: 0.0669

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00668 AC: 9446 AN: 1414862 Hom.: 174 Cov.: 26 AF XY: 0.00652 AC XY: 4589 AN XY: 704186

Gnomad4 AFR exome AF: 0.00301

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00479

Gnomad4 EAS exome AF: 0.0714

Gnomad4 SAS exome AF: 0.00329

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00976 AC: 1466 AN: 150178 Hom.: 41 Cov.: 32 AF XY: 0.0131 AC XY: 959 AN XY: 73228

Gnomad4 AFR AF: 0.00295

Gnomad4 AMR AF: 0.000861

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0698

Gnomad4 SAS AF: 0.00694

Gnomad4 FIN AF: 0.0710

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00771

Bravo AF: 0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2017

This alteration is classified as likely benign based on a combination of the following: 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs138671843; hg19: chr18-59742058;