rs1553259602

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_153747.2(PIGC):ā€‹c.635T>Cā€‹(p.Leu212Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L212R) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

PIGC
NM_153747.2 missense

Scores

13
3
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.79
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 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, 0.937
PP5
Variant 1-172441988-A-G is Pathogenic according to our data. Variant chr1-172441988-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 471154.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-172441988-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PIGCNM_153747.2 linkuse as main transcriptc.635T>C p.Leu212Pro missense_variant 2/2 ENST00000344529.5
C1orf105NM_139240.4 linkuse as main transcriptc.22-3085A>G intron_variant ENST00000367727.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PIGCENST00000344529.5 linkuse as main transcriptc.635T>C p.Leu212Pro missense_variant 2/21 NM_153747.2 P1
C1orf105ENST00000367727.9 linkuse as main transcriptc.22-3085A>G intron_variant 1 NM_139240.4 P1
PIGCENST00000484368.1 linkuse as main transcriptn.96+2000T>C intron_variant, non_coding_transcript_variant 1
PIGCENST00000367728.1 linkuse as main transcriptc.635T>C p.Leu212Pro missense_variant 1/1 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152242
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD4 exome
Cov.:
39
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycosylphosphatidylinositol biosynthesis defect 16 Pathogenic:2
Likely pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsOct 15, 2018This variant is interpreted as Likely Pathogenic, for Glycosylphosphatidylinositol biosynthesis defect 16, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/27694521). PM3-Supporting => PM3 downgraded in strength to Supporting. -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 21, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.22
T;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.83
.;T
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Pathogenic
2.9
M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.3
D;D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.81
Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP
0.79
MPC
0.74
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.97
gMVP
0.95

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: rs1553259602; hg19: chr1-172411128; API