rs1251694138

chr16-574763-G-Achr16-574763-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004204.5(PIGQ):c.689G>A(p.Arg230Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000213 in 1,407,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. 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. R230G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIGQ NM_004204.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGQ	NM_004204.5	c.689G>A	p.Arg230Gln	missense_variant, splice_region_variant	2/11	ENST00000321878.10
PIGQ	NM_148920.4	c.689G>A	p.Arg230Gln	missense_variant, splice_region_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGQ	ENST00000321878.10	c.689G>A	p.Arg230Gln	missense_variant, splice_region_variant	2/11	1	NM_004204.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000152 AC: 3 AN: 197560 Hom.: 0 AF XY: 0.00000921 AC XY: 1 AN XY: 108582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000980

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000213 AC: 3 AN: 1407398 Hom.: 0 Cov.: 33 AF XY: 0.00000288 AC XY: 2 AN XY: 695626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2017

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PIGQ-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 230 of the PIGQ protein (p.Arg230Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 2 of the PIGQ coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	41
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.20	N;N;D;N;D
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Benign	0.26	T;T;D;T;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.56
MutPred		0.65		Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);Loss of MoRF binding (P = 0.0933);
MVP		0.67
MPC		0.45
ClinPred		0.63	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1251694138; hg19: chr16-624763;