ENST00000470411.2:c.*206G>A

Variant names:

• chr16-576255-G-A
• rs200661329
• ENST00000470411.2:c.*206G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The ENST00000470411.2(PIGQ):​c.*206G>A variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 1,555,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PIGQ ENST00000470411.2 3_prime_UTR
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.52
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 77

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000282907 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-576255-G-A is Pathogenic according to our data. Variant chr16-576255-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGQ	NM_004204.5	c.942+1G>A		splice_donor_variant, intron_variant	Intron 4 of 10	ENST00000321878.10	NP_004195.2
PIGQ	NM_148920.4	c.942+1G>A		splice_donor_variant, intron_variant	Intron 4 of 9		NP_683721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGQ	ENST00000321878.10	c.942+1G>A		splice_donor_variant, intron_variant	Intron 4 of 10	1	NM_004204.5	ENSP00000326674.6

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000568 AC: 9 AN: 158484 AF XY: 0.0000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000221 AC: 31 AN: 1403020 Hom.: 0 Cov.: 34 AF XY: 0.0000188 AC XY: 13 AN XY: 692668

African (AFR) AF: 0.0000312 AC: 1 AN: 32080

American (AMR) AF: 0.000357 AC: 13 AN: 36446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36540

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1082000

Other (OTH) AF: 0.0000172 AC: 1 AN: 58146

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152372 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000612 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.00000896 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 77 Pathogenic:3

Jan 26, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PIGQ c.942+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 5.7e-05 in 158484 control chromosomes (gnomAD). One in silico tool predicts damaging effect on splicing for this variant (TraP Score: 0.9). However, these predictions have not been tested experimentally. c.942+1G>A has been reported in the literature in individuals affected with PIGQ related conditions (example: Johnstone_2020 and Burstein_PR_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2, PM3 -

PIGQ-related disorder Pathogenic:2

May 25, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PIGQ c.942+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in two individuals with early infantile epileptic encephalopathy (Johnstone et al. 2020. PubMed ID: 32588908). This variant is reported in 0.024% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in PIGQ are expected to be pathogenic. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Jul 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.942+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 4 (coding exon 3) of the PIGQ gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (9/158484) total alleles studied. The highest observed frequency was 0.02% (6/25454) of Latino alleles. The c.942+1G>A alteration has been described in trans with a second disease-causing alteration in a patient with seizures, developmental delay, truncal hypotonia, abnormal movements, feeding issues, facial dysmorphism, and anomalies of the skeletal, ophthalmological, cardiac, gastrointestinal, and genitourinary systems (Johnstone, 2020). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Mar 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with another PIGQ variant on the opposite allele (in trans) in a patient with pediatric cardiomyopathy in the published literature, however, further clinical information was not provided (PMID: 37923198); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32746448, 37923198, 32588908, 38456468) -

Epilepsy Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the PIGQ gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGQ are known to be pathogenic (PMID: 24463883, 25558065). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with PIGQ-related conditions (PMID: 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: 453003). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.5
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200661329; hg19: chr16-626255;