rs144613953

Variant names:

• chr16-582262-C-A
• rs144613953
• NM_004204.5:c.1546C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-582262-C-A
• chr16-582262-C-T

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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. R516H) 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:3
• Conservation: PhyloP100: 1.17
• Publications: 4 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD gene

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.1546C>A	p.Arg516Ser	missense	Exon 10 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.1532-621C>A		intron	N/A	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.1546C>A	p.Arg516Ser	missense	Exon 10 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000026218.9	TSL:1	c.1532-621C>A		intron	N/A	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000854227.1		c.1708C>A	p.Arg570Ser	missense	Exon 11 of 12	ENSP00000524286.1

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

GnomAD2 exomes AF: 0.00159 AC: 379 AN: 239062 AF XY: 0.00164

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 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

African (AFR) AF: 0.000420 AC: 14 AN: 33362

American (AMR) AF: 0.00193 AC: 86 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.0000769 AC: 2 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.000984 AC: 84 AN: 85394

European-Finnish (FIN) AF: 0.000390 AC: 20 AN: 51344

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.00293 AC: 3246 AN: 1108790

Other (OTH) AF: 0.00188 AC: 113 AN: 60070

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

African (AFR) AF: 0.000289 AC: 12 AN: 41586

American (AMR) AF: 0.00157 AC: 24 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00210 Hom.: 26

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 77 (1)
-	-	1	Epilepsy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
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
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Benign	0.063	T
Sift4G	Uncertain	0.034	D
Polyphen		0.20	B
Vest4		0.70
MVP		0.33
ClinPred		0.015	T
GERP RS		2.8
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs144613953; hg19: chr16-632262;