rs768633670
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153682.3(PIGP):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,038 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 0 hom. )
Consequence
PIGP
NM_153682.3 start_lost
NM_153682.3 start_lost
Scores
3
9
4
Clinical Significance
Conservation
PhyloP100: 7.28
Genes affected
PIGP (HGNC:3046): (phosphatidylinositol glycan anchor biosynthesis class P) This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells that serves to anchor proteins to the cell surface. The encoded protein is a component of the GPI-N-acetylglucosaminyltransferase complex that catalyzes the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This gene is located in the Down Syndrome critical region on chromosome 21 and is a candidate for the pathogenesis of Down syndrome. This gene has multiple pseudogenes and is a member of the phosphatidylinositol glycan anchor biosynthesis gene family. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 21-37072514-A-G is Pathogenic according to our data. Variant chr21-37072514-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-37072514-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIGP | NM_153682.3 | c.2T>C | p.Met1? | start_lost | 2/5 | ENST00000360525.9 | |
PIGP | NM_001320480.2 | c.2T>C | p.Met1? | start_lost | 2/5 | ||
PIGP | NM_153681.2 | c.74T>C | p.Met25Thr | missense_variant | 1/4 | ||
PIGP | NM_016430.4 | c.-243T>C | 5_prime_UTR_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGP | ENST00000360525.9 | c.2T>C | p.Met1? | start_lost | 2/5 | 1 | NM_153682.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251494Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135922
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GnomAD4 exome AF: 0.0000773 AC: 113AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54AN XY: 727234
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 55 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 23, 2021 | ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM3 moderate, PP1 supporting - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 11, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.2T>C;p.(Met1?) is a start-loss variant in the PIGP gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28334793) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 397551; PMID: 28334793; 32042915; 31139695) - PS4. The variant is present at low allele frequencies population databases (rs768633670 - gnomAD 0.0003943%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Met1?) was detected in trans with a pathogenic variant (PMID: 28334793; 32042915) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 10, 2020 | ACMG classification criteria: PS3, PS4, PM2, PM3 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the PIGP protein (p.Met25Thr). This variant is present in population databases (rs768633670, gnomAD 0.006%). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 28334793). 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: 397551). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PIGP function (PMID: 28334793). For these reasons, this variant has been classified as Pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, no assertion criteria provided | research | Care4Rare-SOLVE, CHEO | Feb 23, 2017 | This variant was found in a compound heterozygous state with c.456delA. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;T;D;D
Polyphen
1.0
.;D;.;.
Vest4
MVP
MPC
0.045
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at