Menu
GeneBe

1-172442093-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_153747.2(PIGC):c.530T>C(p.Leu177Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L177L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PIGC
NM_153747.2 missense

Scores

11
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.74
Variant links:
Genes affected
PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]
C1orf105 (HGNC:29591): (chromosome 1 open reading frame 105)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_153747.2
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PIGCNM_153747.2 linkuse as main transcriptc.530T>C p.Leu177Pro missense_variant 2/2 ENST00000344529.5
C1orf105NM_139240.4 linkuse as main transcriptc.22-2980A>G intron_variant ENST00000367727.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PIGCENST00000344529.5 linkuse as main transcriptc.530T>C p.Leu177Pro missense_variant 2/21 NM_153747.2 P1
C1orf105ENST00000367727.9 linkuse as main transcriptc.22-2980A>G intron_variant 1 NM_139240.4 P1
PIGCENST00000484368.1 linkuse as main transcriptn.96+1895T>C intron_variant, non_coding_transcript_variant 1
PIGCENST00000367728.1 linkuse as main transcriptc.530T>C p.Leu177Pro missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251426
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461888
Hom.:
0
Cov.:
39
AF XY:
0.00000963
AC XY:
7
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 07, 2023This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 177 of the PIGC protein (p.Leu177Pro). This variant is present in population databases (rs372409223, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PIGC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1924079). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGC protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.24
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Benign
0.40
T;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Benign
-0.54
T
MutationAssessor
Pathogenic
3.1
M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.95
P;P
Vest4
0.99
MVP
0.81
MPC
0.53
ClinPred
0.87
D
GERP RS
5.2
Varity_R
0.96
gMVP
0.98

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.

Other links and lift over

dbSNP: rs372409223; hg19: chr1-172411233; API