18-62154566-C-T

Position:

• chr18-62154566-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_176787.5(PIGN):​c.528G>A​(p.Thr176Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,550,590 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.00

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 18-62154566-C-T is Benign according to our data. Variant chr18-62154566-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 472233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62154566-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00273 (415/152186) while in subpopulation AFR AF= 0.0097 (403/41532). AF 95% confidence interval is 0.00892. There are 3 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.528G>A	p.Thr176Thr	synonymous_variant	7/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.528G>A	p.Thr176Thr	synonymous_variant	7/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.528G>A	p.Thr176Thr	synonymous_variant	6/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.528G>A		non_coding_transcript_exon_variant	5/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152068 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00956

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000702 AC: 174 AN: 247888 Hom.: 2 AF XY: 0.000535 AC XY: 72 AN XY: 134504

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 428 AN: 1398404 Hom.: 4 Cov.: 23 AF XY: 0.000262 AC XY: 183 AN XY: 699358

Gnomad4 AFR exome AF: 0.00982

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000502

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152186 Hom.: 3 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74406

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00130 Hom.: 2

Bravo AF: 0.00306

Asia WGS AF: 0.000868 AC: 3 AN: 3470

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PIGN: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2016

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.7
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs144304758; hg19: chr18-59821799;