16-582287-G-C

Variant names:

• chr16-582287-G-C
• rs143762913
• NM_004204.5:c.1571G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004204.5(PIGQ):​c.1571G>C​(p.Arg524Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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. R524K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73
• 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: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21040171).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004204.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	NM_004204.5	MANE Select	c.1571G>C	p.Arg524Thr	missense	Exon 10 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.1532-596G>C		intron	N/A	NP_683721.1	Q9BRB3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	ENST00000321878.10	TSL:1 MANE Select	c.1571G>C	p.Arg524Thr	missense	Exon 10 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000026218.9	TSL:1	c.1532-596G>C		intron	N/A	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000854227.1		c.1733G>C	p.Arg578Thr	missense	Exon 11 of 12	ENSP00000524286.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451356 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720530

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106226

Other (OTH) AF: 0.00 AC: 0 AN: 59880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.7
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Benign	0.31	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.34
MutPred		0.48		Loss of MoRF binding (P = 0.0174)
MVP		0.27
ClinPred		0.12	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=91/9	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: rs143762913; hg19: chr16-632287;