rs116772777

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001127178.3(PIGG):c.422C>T(p.Ala141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,613,554 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 29)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.388

Variant links:

Genes affected

PIGG (HGNC:25985): (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)) This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

PIGG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007213056).

BP6

Variant 4-505779-C-T is Benign according to our data. Variant chr4-505779-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476349.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00213 (323/151742) while in subpopulation AFR AF= 0.00745 (308/41340). AF 95% confidence interval is 0.00677. There are 1 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3 linkuse as main transcript	c.422C>T	p.Ala141Val	missense_variant	3/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7 linkuse as main transcript	c.422C>T	p.Ala141Val	missense_variant	3/13	1	NM_001127178.3	P4	Q5H8A4-1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

321

AN:

151624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000527

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000449

AC:

113

AN:

251488

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000176

AC:

257

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00663

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.00213

AC:

323

AN:

151742

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.00745

Gnomad4 AMR

AF:

0.000526

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000299

Hom.:

Bravo

AF:

0.00218

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000585

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 53

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 27, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PIGG-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

Cadd

Benign

1.8

Dann

Benign

0.92

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.074

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.0072

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.43

T;T;T;T;T

Sift4G

Benign

0.32

T;T;T;T;T

Polyphen

0.0030

B;B;.;B;B

Vest4

0.13

MVP

0.65

MPC

0.18

ClinPred

0.0034

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over