rs144613953

Positions:

• chr16-582262-C-A
• chr16-582262-C-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.1546C>A​(p.Arg516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,607,022 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict 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. R516C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17

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=0.018725783).
• BP6: Variant 16-582262-C-A is Benign according to our data. Variant chr16-582262-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 456035.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 = 0.00131 (200/152362) while in subpopulation NFE AF= 0.00229 (156/68026). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGQ	NM_004204.5	c.1546C>A	p.Arg516Ser	missense_variant	10/11	ENST00000321878.10
PIGQ	NM_148920.4	c.1532-621C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGQ	ENST00000321878.10	c.1546C>A	p.Arg516Ser	missense_variant	10/11	1	NM_004204.5	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00159 AC: 379 AN: 239062 Hom.: 1 AF XY: 0.00164 AC XY: 214 AN XY: 130456

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00188

GnomAD4 exome AF: 0.00246 AC: 3572 AN: 1454660 Hom.: 12 Cov.: 31 AF XY: 0.00241 AC XY: 1745 AN XY: 723146

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.0000769

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000984

Gnomad4 FIN exome AF: 0.000390

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.00110 AC XY: 82 AN XY: 74504

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00195 Hom.: 14

Bravo AF: 0.00151

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00156 AC: 188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

PIGQ: BP4 -

Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	D;D;D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.063	T;T;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.20	B;B;.
Vest4		0.70
MVP		0.33
ClinPred		0.015	T
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144613953; hg19: chr16-632262;