rs398122394
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM2PP5_Very_Strong
The NM_001099922.3(ALG13):c.320A>G(p.Asn107Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Genomes: not found (cov: 23)
Consequence
ALG13
NM_001099922.3 missense
NM_001099922.3 missense
Scores
5
5
6
Clinical Significance
Conservation
PhyloP100: 8.51
Genes affected
ALG13 (HGNC:30881): (ALG13 UDP-N-acetylglucosaminyltransferase subunit) The protein encoded by this gene is a subunit of a bipartite UDP-N-acetylglucosamine transferase. It heterodimerizes with asparagine-linked glycosylation 14 homolog to form a functional UDP-GlcNAc glycosyltransferase that catalyzes the second sugar addition of the highly conserved oligosaccharide precursor in endoplasmic reticulum N-linked glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PS1
Transcript NM_001099922.3 (ALG13) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-111685040-A-G is Pathogenic according to our data. Variant chrX-111685040-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111685040-A-G is described in Lovd as [Pathogenic]. Variant chrX-111685040-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ALG13 | NM_001099922.3 | c.320A>G | p.Asn107Ser | missense_variant | 3/27 | ENST00000394780.8 | NP_001093392.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ALG13 | ENST00000394780.8 | c.320A>G | p.Asn107Ser | missense_variant | 3/27 | 2 | NM_001099922.3 | ENSP00000378260.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
23
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 36 Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 23, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 12, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Feb 27, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.N107S in ALG13 (NM_001099922.3) has been reported previously as a recurrent mutation in multiple unrelated individuals (Smith-Packard B et al; Ng BG et al). The variant has been submitted to ClinVar as Pathogenic. The p.N107S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.N107S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The asparagine residue at codon 107 of ALG13 is conserved in all mammalian species. The nucleotide c.320 in ALG13 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PS2,PM5,PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences | Jul 15, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 107 of the ALG13 protein (p.Asn107Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile spasms, Lennox-Gastaut syndrome, West syndrome and severe intellectual disability (PMID: 23934111, 24781210, 24896178, 25732998, 26138355, 26482601). In at least one individual the variant was observed to be de novo. This variant is also known as X:110928268 A>G. ClinVar contains an entry for this variant (Variation ID: 66086). 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. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 25, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | research | Cavalleri Lab, Royal College of Surgeons in Ireland | Dec 11, 2019 | ACMG evidence PS1, PS2, PM2, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jan 26, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous missense variant was identified, NM_001099922.2(ALG13):c.320A>G in exon 3 of 27 of the ALG13 gene. This substitution is predicted to create a minor amino acid change from asparagine to serine at position 107 of the protein, NP_001093392.1(ALG13):p.(Asn107Ser). The asparagine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Glyco_tran_28_C functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. An alternative residue change at the same location has been reported in the gnomAD database at a frequency of 0.00055%. The variant has been previously reported pathogenic and de novo in multiple patients with early-onset epileptic encephalopathy (ClinVar, LOVD, Michaud, J. L., et al. (2014), Smith-Packard, B., et al. (2015), Galama, W. H., et al. (2018), Palmer, E. E., et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. - |
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23934111, 26482601, 25877686, 26633542, 28628100, 28778787, 28940310, 28777499, 31444733, 31440721, 32695065, 32238909, 29186148, 30174244, 25732998, 23033978, 24896178, 24781210, 26138355, 27476654, 25533962, 28867141, 29314763, 29190809, 29588952, 28887793, 32681751, 33410528, 31164858, 28191890, 33643843, 33413482, 32978145, 33734437, 32005694, 31785789, 31069529, 35701389) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | May 30, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Intellectual disability Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Dec 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 03, 2020 | The variant c.320A>G, p.(Asn107Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was DNV.The variant likely explains the NDD in this individual. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2017 | The p.N107S pathogenic mutation (also known as c.320A>G), located in coding exon 3 of the ALG13 gene, results from an A to G substitution at nucleotide position 320. The asparagine at codon 107 is replaced by serine, an amino acid with highly similar properties. This mutation has been detected as a de novo occurrence in several individuals with early onset epileptic encephalopathy, infantile spasms, and severe intellectual disability (de Ligt J et al. N. Engl. J. Med., 2012 Nov;367:1921-9; Allen et al. Nature, 2013 Sep;501:217-21; Michaud JL et al. Hum. Mol. Genet., 2014 Sep;23:4846-58; Dimassi S et al. Clin. Genet., 2016 Feb;89:198-204). In one female patient, X-inactivation studies demonstrated a random pattern of X-inactivation, with no evidence of skewness (Hamici S et al. Eur J Med Genet, 2017 Oct;60:541-547). Based on the supporting evidence, p.N107S is interpreted as a disease-causing mutation. - |
Hypotonia;C0036572:Seizure;C4022738:Neurodevelopmental delay;C4551563:Microcephaly Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Mar 18, 2021 | - - |
Rare genetic intellectual disability Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
ALG13-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 18, 2023 | The ALG13 c.320A>G variant is predicted to result in the amino acid substitution p.Asn107Ser. This variant has been reported repeatedly to be causative for Lennox-Gastaut Syndrome, early-onset epileptic encephalopathy, infantile spasms and West syndrome (reported as X:110928268A>G in Allen et al. 2013. PubMed ID: 23934111; Myers et al. 2016. PubMed ID: 27476654; Bastaki et al. 2018. PubMed ID: 28940310). It has been documented as a recurrent de novo variant in female individuals with ALG13-related presentations (e.g. Table 1, Ortega-Moreno et al. 2017. PubMed ID: 29190809; Table 1, Kobayashi et al. 2016. PubMed ID: 26482601). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Seizure Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Oct 29, 2020 | Recurrent pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;.;.;T;.;D;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;.;D;D;D;D;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;N;.;N;.;.;.;.;.;.;.
REVEL
Benign
Sift
Pathogenic
D;D;.;D;.;.;.;.;.;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;B;B;B;B;.;.;.;B;.;.
Vest4
MutPred
Gain of disorder (P = 0.0968);Gain of disorder (P = 0.0968);.;.;.;Gain of disorder (P = 0.0968);Gain of disorder (P = 0.0968);.;.;.;.;
MVP
MPC
0.64
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at