Genetic Variant PIGQ:p.Arg425Gln (chr16-579119-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004204.5(PIGQ):c.1274G>A(p.Arg425Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,666 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. R425W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PIGQ
NM_004204.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.07

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGQ	NM_004204.5 link	c.1274G>A	p.Arg425Gln	missense_variant	Exon 7 of 11	ENST00000321878.10	NP_004195.2	Q9BRB3-2B2RAU6
PIGQ	NM_148920.4 link	c.1274G>A	p.Arg425Gln	missense_variant	Exon 7 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.1274G>A	p.Arg425Gln	missense_variant	Exon 7 of 11	1	NM_004204.5	ENSP00000326674.6		Q9BRB3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111766

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

.;.;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.4

M;M;M;.

PhyloP100

8.1

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.99

D;D;D;.

Vest4

0.92

MutPred

0.74

Gain of methylation at K428 (P = 0.0548);Gain of methylation at K428 (P = 0.0548);Gain of methylation at K428 (P = 0.0548);.;

MVP

0.67

MPC

0.61

ClinPred

0.99

GERP RS

5.8

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.81

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

0.40

Position offset: -50

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