rs766667249

chr16-578911-TCTA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_004204.5(PIGQ):c.1199_1201del(p.Tyr400del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PIGQ NM_004204.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.47

Genes affected

PIGQ (HGNC:14135): (phosphatidylinositol glycan anchor biosynthesis class Q) This gene is involved in the first step 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 gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004204.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-578911-TCTA-T is Pathogenic according to our data. Variant chr16-578911-TCTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGQ	NM_004204.5	c.1199_1201del	p.Tyr400del	inframe_deletion	6/11	ENST00000321878.10
PIGQ	NM_148920.4	c.1199_1201del	p.Tyr400del	inframe_deletion	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGQ	ENST00000321878.10	c.1199_1201del	p.Tyr400del	inframe_deletion	6/11	1	NM_004204.5	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151672 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250380 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1460902 Hom.: 0 AF XY: 0.000215 AC XY: 156 AN XY: 726798

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.000275

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151788 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74126

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000954

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2021	In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27513193, 31148362, 32746448) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PIGQ: PM3:Very Strong, PM2, PM4, PS3:Supporting -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The c.1199_1201delACT (p.Y400del) alteration is located in exon 6 (coding exon 5) of the PIGQ gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions 1199 and 1201, resulting in the deletion of a tyrosine (Y) at amino acid position 400. Based on data from the Genome Aggregation Database (gnomAD) database, the PIGQ c.1199_1201delACT alteration was observed in 0.014% (40/281,686) of total alleles studied, with a frequency of 0.03% (37/128,562) in the European (non-Finnish) subpopulation. The p.Y400del alteration has been reported in trans with a second PIGQ alteration in multiple patients with infantile epileptic encephalopathy (Johnstone, 2020). The p.Y400 amino acid is conserved in available vertebrate species. The p.Y400 amino acid is located in the third transmembrane region of the PIGQ catalytic domain. The p.Y400del alteration is predicted to be deleterious with a score of -16.01 by PROVEAN in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This variant, c.1199_1201del, results in the deletion of 1 amino acid(s) of the PIGQ protein (p.Tyr400del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766667249, gnomAD 0.03%). This variant has been observed in individual(s) with PIGQ-related conditions (PMID: 31148362, 32588908). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449630). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 77 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs766667249; hg19: chr16-628911;