NM_004204.5:c.892G>T

Variant names:

• chr16-576204-G-T
• rs750484214
• NM_004204.5:c.892G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004204.5(PIGQ):​c.892G>T​(p.Gly298Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G298R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27126855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGQ	NM_004204.5	c.892G>T	p.Gly298Trp	missense_variant	Exon 4 of 11	ENST00000321878.10	NP_004195.2
PIGQ	NM_148920.4	c.892G>T	p.Gly298Trp	missense_variant	Exon 4 of 10		NP_683721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGQ	ENST00000321878.10	c.892G>T	p.Gly298Trp	missense_variant	Exon 4 of 11	1	NM_004204.5	ENSP00000326674.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 154298 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398098 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689700

African (AFR) AF: 0.00 AC: 0 AN: 31664

American (AMR) AF: 0.00 AC: 0 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35830

South Asian (SAS) AF: 0.00 AC: 0 AN: 79280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079188

Other (OTH) AF: 0.0000172 AC: 1 AN: 58002

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy Uncertain:1

Apr 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with PIGQ-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 298 of the PIGQ protein (p.Gly298Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.057	.;.;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;N;.;N
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N;D;N
REVEL	Benign	0.16
Sift	Benign	0.063	T;T;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.20	B;B;.;D
Vest4		0.45
MutPred		0.69		Loss of loop (P = 0.0145);Loss of loop (P = 0.0145);Loss of loop (P = 0.0145);Loss of loop (P = 0.0145);
MVP		0.41
MPC		0.42
ClinPred		0.92	D
GERP RS		-2.4
Varity_R		0.042
gMVP		0.38
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs750484214; hg19: chr16-626204;