rs371210440

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000321878.10(PIGQ):c.902G>A(p.Arg301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,550,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R301C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PIGQ
ENST00000321878.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030323386).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000407 (62/152224) while in subpopulation AMR AF= 0.00288 (44/15288). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGQ	NM_004204.5 linkuse as main transcript	c.902G>A	p.Arg301His	missense_variant	4/11	ENST00000321878.10	NP_004195.2
PIGQ	NM_148920.4 linkuse as main transcript	c.902G>A	p.Arg301His	missense_variant	4/10		NP_683721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGQ	ENST00000321878.10 linkuse as main transcript	c.902G>A	p.Arg301His	missense_variant	4/11	1	NM_004204.5	ENSP00000326674	P1	Q9BRB3-2

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000285

AC:

AN:

154524

Hom.:

AF XY:

0.000355

AC XY:

AN XY:

81590

show subpopulations

Gnomad AFR exome

AF:

0.000114

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000457

GnomAD4 exome

AF:

0.000191

AC:

267

AN:

1398534

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

125

AN XY:

689966

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00100

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000630

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000407

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000478

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2021

The c.902G>A (p.R301H) alteration is located in exon 4 (coding exon 3) of the PIGQ gene. This alteration results from a G to A substitution at nucleotide position 902, causing the arginine (R) at amino acid position 301 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

PIGQ: PM2, BP4 -

Epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 301 of the PIGQ protein (p.Arg301His). This variant is present in population databases (rs371210440, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PIGQ-related conditions. ClinVar contains an entry for this variant (Variation ID: 574611). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.040

.;.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.86

.;D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.63

N;N;.;N

MutationTaster

Benign

0.67

D;D;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.66

N;N;D;N

REVEL

Benign

0.038

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.30

T;T;D;T

Polyphen

0.010

B;B;.;B

Vest4

0.34

MVP

0.56

MPC

0.18

ClinPred

0.0046

GERP RS

1.8

Varity_R

0.026

gMVP

0.28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over