Genetic Variant PIGQ:p.Leu309Phe (chr16-576237-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004204.5(PIGQ):c.925C>T(p.Leu309Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,401,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L309V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PIGQ
NM_004204.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79

Publications

0 publications found

Variant links:

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

PIGQ links:

ENSG00000282907 (HGNC:):

ENSG00000282907 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGQ	NM_004204.5 link	c.925C>T	p.Leu309Phe	missense_variant	Exon 4 of 11	ENST00000321878.10	NP_004195.2	Q9BRB3-2B2RAU6
PIGQ	NM_148920.4 link	c.925C>T	p.Leu309Phe	missense_variant	Exon 4 of 10		NP_683721.1	Q9BRB3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGQ	ENST00000321878.10 link	c.925C>T	p.Leu309Phe	missense_variant	Exon 4 of 11	1	NM_004204.5	ENSP00000326674.6		Q9BRB3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1401684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31938

American (AMR)

AF:

0.00

AC:

AN:

36260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

36304

South Asian (SAS)

AF:

0.00

AC:

AN:

79556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1081000

Other (OTH)

AF:

0.00

AC:

AN:

58118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

0.0079

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

.;.;.;T

Eigen

Benign

0.077

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.2

L;L;.;L

PhyloP100

3.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

N;N;D;N

REVEL

Benign

0.29

Sift

Benign

0.086

T;T;D;T

Sift4G

Benign

0.085

T;T;D;D

Polyphen

0.75

P;P;.;P

Vest4

0.67

MutPred

0.73

Gain of catalytic residue at L309 (P = 0.1014);Gain of catalytic residue at L309 (P = 0.1014);Gain of catalytic residue at L309 (P = 0.1014);Gain of catalytic residue at L309 (P = 0.1014);

MVP

0.77

MPC

0.32

ClinPred

0.79

GERP RS

5.4

Varity_R

0.16

gMVP

0.66

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over