rs369486176
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_176787.5(PIGN):c.1434+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,595,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.0000066 ( 0 hom., cov: 32)
Exomes ๐: 0.000011 ( 0 hom. )
Consequence
PIGN
NM_176787.5 splice_donor_5th_base, intron
NM_176787.5 splice_donor_5th_base, intron
Scores
1
4
Clinical Significance
Conservation
PhyloP100: 3.19
Genes affected
PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-62113129-C-T is Pathogenic according to our data. Variant chr18-62113129-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 264636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62113129-C-T is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.22355253).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGN | NM_176787.5 | c.1434+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000640252.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGN | ENST00000640252.2 | c.1434+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_176787.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
152114
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000177 AC: 4AN: 226090Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 122118
GnomAD3 exomes
AF:
AC:
4
AN:
226090
Hom.:
AF XY:
AC XY:
0
AN XY:
122118
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000111 AC: 16AN: 1443568Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 8AN XY: 716772
GnomAD4 exome
AF:
AC:
16
AN:
1443568
Hom.:
Cov.:
28
AF XY:
AC XY:
8
AN XY:
716772
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304
GnomAD4 genome
?
AF:
AC:
1
AN:
152114
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74304
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
3
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple congenital anomalies-hypotonia-seizures syndrome 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice region variant c.1434+5G>A in PIGN (NM_176787.5) has been reported previously in affected indivduals (Fleming L et al). The variant as been submitted to ClinVar as Likely Pathogenic. The c.1434+5G>A variant is observed in 1/28,292 (0.0035%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The nucleotide c.1434+5G>A in PIGN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change falls in intron 16 of the PIGN gene. It does not directly change the encoded amino acid sequence of the PIGN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369486176, gnomAD 0.004%). This variant has been observed in individual(s) with PIGN-related conditions (PMID: 26394714, 34051595, 35179230). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264636). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | The NM_176787:exon17:c.1434+5G>A splice site mutation is a known pathogenic variant that has been maternally inherited. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2021 | In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 34051595, 27535533, 27038415, 26394714) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Oct 23, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T
MutationTaster
Benign
A;A
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at