rs56293456

Variant names:

• chr16-574149-G-A
• rs56293456
• NM_004204.5:c.75G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004204.5(PIGQ):​c.75G>A​(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,302 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (18 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (22 hom.)
• Consequence: PIGQ NM_004204.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.84
• Publications: 2 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: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000282907 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-574149-G-A is Benign according to our data. Variant chr16-574149-G-A is described in ClinVar as Benign. ClinVar VariationId is 456053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00649 (988/152348) while in subpopulation AFR AF = 0.0203 (842/41580). AF 95% confidence interval is 0.0191. There are 18 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.75G>A	p.Pro25Pro	synonymous	Exon 2 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.75G>A	p.Pro25Pro	synonymous	Exon 2 of 10	NP_683721.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	ENST00000321878.10	TSL:1 MANE Select	c.75G>A	p.Pro25Pro	synonymous	Exon 2 of 11	ENSP00000326674.6
	PIGQ	ENST00000026218.9	TSL:1	c.75G>A	p.Pro25Pro	synonymous	Exon 2 of 10	ENSP00000026218.5
	PIGQ	ENST00000470411.2	TSL:1	c.75G>A	p.Pro25Pro	synonymous	Exon 2 of 3	ENSP00000439650.1

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 989 AN: 152230 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00344 AC: 851 AN: 247642 AF XY: 0.00340

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000929

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00136 AC: 1979 AN: 1459954 Hom.: 22 Cov.: 40 AF XY: 0.00151 AC XY: 1094 AN XY: 726356

African (AFR) AF: 0.0208 AC: 696 AN: 33472

American (AMR) AF: 0.00107 AC: 48 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00277 AC: 110 AN: 39690

South Asian (SAS) AF: 0.0110 AC: 950 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51966

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111690

Other (OTH) AF: 0.00230 AC: 139 AN: 60348

GnomAD4 genome AF: 0.00649 AC: 988 AN: 152348 Hom.: 18 Cov.: 34 AF XY: 0.00624 AC XY: 465 AN XY: 74510

African (AFR) AF: 0.0203 AC: 842 AN: 41580

American (AMR) AF: 0.00229 AC: 35 AN: 15312

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

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5188

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4830

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00668

Asia WGS AF: 0.0130 AC: 48 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy (1)
-	-	1	not provided (1)
-	-	1	PIGQ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.81
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs56293456; hg19: chr16-624149;