rs138345843

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127178.3(PIGG):c.2204G>A(p.Arg735Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,613,522 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R735W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 4 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.77

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 53
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

PIGG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.013729483).

BP6

Variant 4-527173-G-A is Benign according to our data. Variant chr4-527173-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476334.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 = 0.00261 (397/152294) while in subpopulation AFR AF = 0.00907 (377/41564). AF 95% confidence interval is 0.00832. There are 7 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGG	NM_001127178.3 link	c.2204G>A	p.Arg735Gln	missense_variant	Exon 10 of 13	ENST00000453061.7	NP_001120650.1	Q5H8A4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7 link	c.2204G>A	p.Arg735Gln	missense_variant	Exon 10 of 13	1	NM_001127178.3	ENSP00000415203.2		Q5H8A4-1

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

395

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000591

AC:

147

AN:

248878

AF XY:

0.000490

show subpopulations

Gnomad AFR exome

AF:

0.00821

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461228

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.00924

AC:

309

AN:

33452

American (AMR)

AF:

0.000314

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111830

Other (OTH)

AF:

0.000513

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00261

AC:

397

AN:

152294

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00907

AC:

377

AN:

41564

American (AMR)

AF:

0.00105

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000580

Hom.:

Bravo

AF:

0.00302

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jun 24, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIGG: BP4, BS2 -

Intellectual disability, autosomal recessive 53

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PIGG-related disorder

Benign:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Intellectual disability, autosomal recessive 53;C5676953:BLOOD GROUP, EMM SYSTEM

Benign:1

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.079

.;T;T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

2.9

.;M;.;.

PhyloP100

8.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0090

D;D;D;T

Sift4G

Uncertain

0.024

D;T;T;T

Polyphen

1.0

D;D;.;D

Vest4

0.83

MVP

0.44

MPC

0.75

ClinPred

0.057

GERP RS

6.2

Varity_R

0.39

gMVP

0.77

Mutation Taster

=84/16

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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rs138345843

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over