rs104894490
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_144599.5(NIPA1):c.316G>A(p.Gly106Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NIPA1
NM_144599.5 missense, splice_region
NM_144599.5 missense, splice_region
Scores
3
3
3
Splicing: ADA: 0.9928
2
Clinical Significance
Conservation
PhyloP100: 7.42
Genes affected
NIPA1 (HGNC:17043): (NIPA magnesium transporter 1) This gene encodes a magnesium transporter that associates with early endosomes and the cell surface in a variety of neuronal and epithelial cells. This protein may play a role in nervous system development and maintenance. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with autosomal dominant spastic paraplegia 6. [provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856
PP5
Variant 15-22812252-G-A is Pathogenic according to our data. Variant chr15-22812252-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-22812252-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NIPA1 | NM_144599.5 | c.316G>A | p.Gly106Arg | missense_variant, splice_region_variant | 3/5 | ENST00000337435.9 | NP_653200.2 | |
| NIPA1 | NM_001142275.1 | c.91G>A | p.Gly31Arg | missense_variant, splice_region_variant | 3/5 | NP_001135747.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1452338Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 723148
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1452338
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Cov.:
27
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0
AN XY:
723148
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 6 Pathogenic:6
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.G106R in NIPA1 (NM_144599.5) has been reported previously in affected patients (Hedera P et al; Morais S et al). The variant has been previously reported as de novo mutation. The variant has been submitted to ClinVar as Pathogenic. The p.G106R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G106R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 106 of NIPA1 is conserved in all mammalian species. The nucleotide c.316 in NIPA1 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 | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 03, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PM5,PP3,PP5. - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the NIPA1 protein (p.Gly106Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia (HSP) (PMID: 15643603, 15711826, 16267846, 21599812, 22302102, 24075313). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as G341A. ClinVar contains an entry for this variant (Variation ID: 2523). 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 NIPA1 function (PMID: 17166836, 19091982, 19620182, 20816793, 24128679). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 07, 2024 | This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. This variant results in the same amino acid change as another variant considered to be pathogenic (c.316G>C). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID 17166836, 19091982, 20816793) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
| 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 | Eurofins Ntd Llc (ga) | Jan 12, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 28, 2021 | PP1, PM2, PM6, PS1, PS3, PS4_moderate - |
Hereditary spastic paraplegia Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 03, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde | Mar 07, 2017 | - - |
Spastic paraplegia Pathogenic:1
| Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D
LIST_S2
Uncertain
.;D;D
MetaRNN
Pathogenic
D;D;D
PROVEAN
Benign
N;N;N
Sift
Benign
D;D;D
Sift4G
Benign
.;.;T
Vest4
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at