16-582974-G-T

Variant names:

• chr16-582974-G-T
• rs372069327
• NM_004204.5:c.1685G>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.1685G>T​(p.Arg562Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R562H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.318173).

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.1685G>T	p.Arg562Leu	missense	Exon 11 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.1623G>T	p.Pro541Pro	synonymous	Exon 10 of 10	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.1685G>T	p.Arg562Leu	missense	Exon 11 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000026218.9	TSL:1	c.1623G>T	p.Pro541Pro	synonymous	Exon 10 of 10	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000854227.1		c.1847G>T	p.Arg616Leu	missense	Exon 12 of 12	ENSP00000524286.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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	0.17
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.9
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.051	T
Sift4G	Benign	0.093	T
Polyphen		0.66	P
Vest4		0.65
MutPred		0.48		Gain of ubiquitination at K563 (P = 0.0445)
MVP		0.62
ClinPred		0.80	D
GERP RS		4.3

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: rs372069327; hg19: chr16-632974;