chr4-500399-C-A

Position:

chr4-500399-C-A

Variant summary

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

The NM_001127178.3(PIGG):c.158C>A(p.Ala53Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,611,608 control chromosomes in the GnomAD database, including 45 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 22 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.510

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017834306).

BP6

Variant 4-500399-C-A is Benign according to our data. Variant chr4-500399-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 376911.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 = 0.00863 (1313/152228) while in subpopulation AFR AF= 0.0301 (1249/41506). AF 95% confidence interval is 0.0287. There are 23 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGG	NM_001127178.3 link	c.158C>A	p.Ala53Asp	missense_variant	2/13	ENST00000453061.7	NP_001120650.1	Q5H8A4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7 link	c.158C>A	p.Ala53Asp	missense_variant	2/13	1	NM_001127178.3	ENSP00000415203.2		Q5H8A4-1

Frequencies

GnomAD3 genomes

AF:

0.00863

AC:

1313

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00209

AC:

526

AN:

251194

Hom.:

AF XY:

0.00150

AC XY:

204

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000873

AC:

1274

AN:

1459380

Hom.:

Cov.:

AF XY:

0.000742

AC XY:

539

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.0295

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000901

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00863

AC:

1313

AN:

152228

Hom.:

Cov.:

AF XY:

0.00834

AC XY:

621

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0301

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.00961

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00266

AC:

323

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Intellectual disability, autosomal recessive 53

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0074

.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.44

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

L;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.030

Sift

Benign

0.18

T;T;D

Sift4G

Benign

0.65

T;T;T

Polyphen

0.52

P;B;B

Vest4

0.21

MVP

0.17

MPC

0.25

ClinPred

0.0026

GERP RS

1.6

Varity_R

0.11

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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