chr4-523472-C-G

Position:

chr4-523472-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127178.3(PIGG):c.1628C>G(p.Pro543Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,606,150 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.62

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:

PIGG (HGNC:):

PIGG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042468905).

BP6

Variant 4-523472-C-G is Benign according to our data. Variant chr4-523472-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 476324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00241 (367/152284) while in subpopulation AFR AF= 0.00792 (329/41554). AF 95% confidence interval is 0.00721. There are 3 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGG	NM_001127178.3 linkuse as main transcript	c.1628C>G	p.Pro543Arg	missense_variant	9/13	ENST00000453061.7	NP_001120650.1	Q5H8A4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7 linkuse as main transcript	c.1628C>G	p.Pro543Arg	missense_variant	9/13	1	NM_001127178.3	ENSP00000415203.2		Q5H8A4-1

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00787

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000758

AC:

187

AN:

246850

Hom.:

AF XY:

0.000756

AC XY:

101

AN XY:

133588

show subpopulations

Gnomad AFR exome

AF:

0.00783

Gnomad AMR exome

AF:

0.000234

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000335

AC:

487

AN:

1453866

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

254

AN XY:

721942

show subpopulations

Gnomad4 AFR exome

AF:

0.00747

Gnomad4 AMR exome

AF:

0.000384

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000298

Gnomad4 OTH exome

AF:

0.000767

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152284

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00792

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000408

Hom.:

Bravo

AF:

0.00229

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PIGG: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal recessive 53

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

PIGG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

This variant is classified as 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

0.074

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.4

DANN

Benign

0.76

DEOGEN2

Benign

0.010

.;T;T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;M;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.42

T;T;T;T

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.60

P;P;.;P

Vest4

0.31

MVP

0.26

MPC

0.22

ClinPred

0.011

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.26

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