rs145602990

chr16-580946-G-Achr16-580946-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004204.5(PIGQ):c.1505G>A(p.Arg502Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,610,404 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.00

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067481995).
• BP6: Variant 16-580946-G-A is Benign according to our data. Variant chr16-580946-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000735 (112/152366) while in subpopulation NFE AF= 0.00118 (80/68036). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGQ	NM_004204.5	c.1505G>A	p.Arg502Gln	missense_variant	9/11	ENST00000321878.10
PIGQ	NM_148920.4	c.1505G>A	p.Arg502Gln	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGQ	ENST00000321878.10	c.1505G>A	p.Arg502Gln	missense_variant	9/11	1	NM_004204.5	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00103 AC: 257 AN: 250566 Hom.: 2 AF XY: 0.00115 AC XY: 156 AN XY: 135646

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00141 AC: 2062 AN: 1458038 Hom.: 4 Cov.: 29 AF XY: 0.00143 AC XY: 1040 AN XY: 725572

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74512

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.000884

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00172

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PIGQ-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

PIGQ: BP4 -

Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.23	T;T;D;D
Sift4G	Benign	0.12	T;T;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.88
MVP		0.70
MPC		0.59
ClinPred		0.10	T
GERP RS		5.2
Varity_R		0.33
gMVP		0.86

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

Other links and lift over

dbSNP: rs145602990; hg19: chr16-630946; COSMIC: COSV50312398; COSMIC: COSV50312398;