Variant rs766667249 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_004204.5(PIGQ):c.1199_1201delACT(p.Tyr400del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.47

Variant links:

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]

PIGQ links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
PIGQ	NM_004204.5 link	c.1199_1201delACT	p.Tyr400del	disruptive_inframe_deletion	6/11	ENST00000321878.10	NP_004195.2	Q9BRB3-2B2RAU6
PIGQ	NM_148920.4 link	c.1199_1201delACT	p.Tyr400del	disruptive_inframe_deletion	6/10		NP_683721.1	Q9BRB3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGQ	ENST00000321878.10 link	c.1199_1201delACT	p.Tyr400del	disruptive_inframe_deletion	6/11	1	NM_004204.5	ENSP00000326674.6		Q9BRB3-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

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:

AN:

250380

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135620

show subpopulations

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.:

AF XY:

0.000215

AC XY:

156

AN XY:

726798

show subpopulations

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:

AN:

151788

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74126

show subpopulations

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.:

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

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PIGQ: PM3:Very Strong, PM2, PM4, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27513193, 32588908, 31148362, 32746448, 37923198) -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over