NM_001127178.3:c.2215G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001127178.3(PIGG):​c.2215G>A​(p.Gly739Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,611,902 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G739G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

3
10
6

Clinical Significance

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

Conservation

PhyloP100: 8.77

Publications

4 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.058356762).
BP6
Variant 4-527184-G-A is Benign according to our data. Variant chr4-527184-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542900.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIGGNM_001127178.3 linkc.2215G>A p.Gly739Arg 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
PIGGENST00000453061.7 linkc.2215G>A p.Gly739Arg missense_variant Exon 10 of 13 1 NM_001127178.3 ENSP00000415203.2 Q5H8A4-1

Frequencies

GnomAD3 genomes
AF:
0.000913
AC:
139
AN:
152178
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00924
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000759
AC:
188
AN:
247532
AF XY:
0.000665
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000584
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00674
Gnomad NFE exome
AF:
0.000342
Gnomad OTH exome
AF:
0.000661
GnomAD4 exome
AF:
0.000570
AC:
832
AN:
1459606
Hom.:
1
Cov.:
32
AF XY:
0.000548
AC XY:
398
AN XY:
725986
show subpopulations
African (AFR)
AF:
0.0000599
AC:
2
AN:
33390
American (AMR)
AF:
0.0000450
AC:
2
AN:
44456
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25986
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.0000233
AC:
2
AN:
85942
European-Finnish (FIN)
AF:
0.00696
AC:
371
AN:
53312
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5522
European-Non Finnish (NFE)
AF:
0.000383
AC:
425
AN:
1111078
Other (OTH)
AF:
0.000498
AC:
30
AN:
60264
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
49
98
148
197
246
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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
AF:
0.000913
AC:
139
AN:
152296
Hom.:
1
Cov.:
32
AF XY:
0.00134
AC XY:
100
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41562
American (AMR)
AF:
0.000261
AC:
4
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00924
AC:
98
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000544
AC:
37
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
7
15
22
30
37
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000360
Hom.:
1
Bravo
AF:
0.000253
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000799
AC:
97
EpiCase
AF:
0.000218
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 01, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Intellectual disability, autosomal recessive 53 Benign:1
Jan 25, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
Uncertain
0.38
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;T;T;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.058
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
2.9
.;M;.;.
PhyloP100
8.8
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.4
D;D;D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.97
MutPred
0.78
.;Gain of MoRF binding (P = 0.005);.;.;
MVP
0.48
MPC
0.76
ClinPred
0.29
T
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.58
gMVP
0.83
Mutation Taster
=22/78
disease causing

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

Other links and lift over

dbSNP: rs201269761; hg19: chr4-520973; API