1-172442049-G-A

Position:

chr1-172442049-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_153747.2(PIGC):c.574C>T(p.Arg192Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,876 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PIGC
NM_153747.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.23

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]

PIGC links:

C1orf105 (HGNC:29591): (chromosome 1 open reading frame 105)

C1orf105 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGC	NM_153747.2 link	c.574C>T	p.Arg192Cys	missense_variant	2/2	ENST00000344529.5	NP_714969.1	Q92535
C1orf105	NM_139240.4 link	c.22-3024G>A		intron_variant		ENST00000367727.9	NP_640333.3	O95561

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIGC	ENST00000344529.5 link	c.574C>T	p.Arg192Cys	missense_variant	2/2	1	NM_153747.2	ENSP00000356701.3	Q92535
C1orf105	ENST00000367727.9 link	c.22-3024G>A		intron_variant		1	NM_139240.4	ENSP00000356700.4	O95561
PIGC	ENST00000484368.1 link	n.96+1939C>T		intron_variant		1
PIGC	ENST00000367728.1 link	c.574C>T	p.Arg192Cys	missense_variant	1/1	6		ENSP00000356702.1	Q92535

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2024

The c.574C>T (p.R192C) alteration is located in exon 2 (coding exon 1) of the PIGC gene. This alteration results from a C to T substitution at nucleotide position 574, causing the arginine (R) at amino acid position 192 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Glycosylphosphatidylinositol biosynthesis defect 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 03, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the PIGC protein (p.Arg192Cys). This variant is present in population databases (rs768479943, gnomAD 0.0009%). 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: 1402737). 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

0.71

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

-0.074

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.91

P;P

Vest4

0.94

MutPred

0.95

Gain of catalytic residue at L193 (P = 0.0082);Gain of catalytic residue at L193 (P = 0.0082);

MVP

0.84

MPC

0.26

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.94

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