chr16-576237-C-G

Variant names:

• chr16-576237-C-G
• rs145216283
• NM_004204.5:c.925C>G

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.925C>G​(p.Leu309Val) variant causes a missense change. The variant allele was found at a frequency of 0.00183 in 1,554,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L309L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.79
• 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

ENSG00000282907 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017574817).
• BP6: Variant 16-576237-C-G is Benign according to our data. Variant chr16-576237-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 526287.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 = 0.000991 (151/152366) while in subpopulation NFE AF = 0.00179 (122/68028). AF 95% confidence interval is 0.00153. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.925C>G	p.Leu309Val	missense	Exon 4 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.925C>G	p.Leu309Val	missense	Exon 4 of 10	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.925C>G	p.Leu309Val	missense	Exon 4 of 11	ENSP00000326674.6	Q9BRB3-2
	PIGQ	ENST00000026218.9	TSL:1	c.925C>G	p.Leu309Val	missense	Exon 4 of 10	ENSP00000026218.5	Q9BRB3-1
	PIGQ	ENST00000470411.2	TSL:1	c.*188C>G		3_prime_UTR	Exon 3 of 3	ENSP00000439650.1	Q9BRB3-3

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00109 AC: 172 AN: 157760 AF XY: 0.00111

Gnomad AFR exome AF: 0.000654

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000726

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.00192 AC: 2686 AN: 1401684 Hom.: 3 Cov.: 34 AF XY: 0.00183 AC XY: 1268 AN XY: 691786

African (AFR) AF: 0.000282 AC: 9 AN: 31938

American (AMR) AF: 0.000386 AC: 14 AN: 36260

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 37 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36304

South Asian (SAS) AF: 0.000679 AC: 54 AN: 79556

European-Finnish (FIN) AF: 0.000440 AC: 21 AN: 47774

Middle Eastern (MID) AF: 0.000361 AC: 2 AN: 5542

European-Non Finnish (NFE) AF: 0.00230 AC: 2484 AN: 1081000

Other (OTH) AF: 0.00112 AC: 65 AN: 58118

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000953 AC XY: 71 AN XY: 74498

African (AFR) AF: 0.000289 AC: 12 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000700 AC: 3

ESP6500EA AF: 0.00142 AC: 12

ExAC AF: 0.000697 AC: 77

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epilepsy (1)
-	-	1	PIGQ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	0.072
Eigen_PC	Benign	0.072
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.28
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.75	P
Vest4		0.61
MVP		0.63
MPC		0.41
ClinPred		0.024	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.59
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs145216283; hg19: chr16-626237;