Human Gene Module / Chromosome 15 / NIPA1

NIPA1non imprinted in Prader-Willi/Angelman syndrome 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
6 / 0
Aliases
NIPA1, FSP3,  SPG6
Associated Syndromes
-
Chromosome Band
15q11.2
Associated Disorders
ID
Relevance to Autism

A rare NIPA1 deletion was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012).

Molecular Function

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.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to NIPA1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6) Rainier S , et al. (2003) No -
2 Support A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia Reed JA , et al. (2005) No -
3 Support A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder van der Zwaag B , et al. (2009) Yes -
4 Primary Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders Leblond CS , et al. (2012) Yes ID
5 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.907G>A p.Val303Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
c.907G>A p.Val303Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Paternal Multi-generational 20029941 van der Zwaag B , et al. (2009)
c.661C>T p.Pro221Ser missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.672G>C p.Gln224His missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

NIPA1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). Rainier et al., 2003 had previously determined that NIPA1 is highly expressed in neuronal tissues. A rare maternally-inherited missense variant in NIPA1 was observed in a male patient with ASD and speech delay in Brett et al., 2014; however, in silico analysis predicted that this variant was likely benign in effect. Heterozygous variants in the NIPA1 gene are also associated with a form of autosomal dominant spastic paraplegia (SPG6; OMIM 600363) (Rainier et al., 2003; Reed et al., 2005).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

NIPA1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). Rainier et al., 2003 had previously determined that NIPA1 is highly expressed in neuronal tissues. A rare maternally-inherited missense variant in NIPA1 was observed in a male patient with ASD and speech delay in Brett et al., 2014; however, in silico analysis predicted that this variant was likely benign in effect. Heterozygous variants in the NIPA1 gene are also associated with a form of autosomal dominant spastic paraplegia (SPG6; OMIM 600363) (Rainier et al., 2003; Reed et al., 2005).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

NIPA1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). Rainier et al., 2003 had previously determined that NIPA1 is highly expressed in neuronal tissues. A rare maternally-inherited missense variant in NIPA1 was observed in a male patient with ASD and speech delay in Brett et al., 2014; however, in silico analysis predicted that this variant was likely benign in effect. Heterozygous variants in the NIPA1 gene are also associated with a form of autosomal dominant spastic paraplegia (SPG6; OMIM 600363) (Rainier et al., 2003; Reed et al., 2005).

Reports Added
[New Scoring Scheme]
10/1/2017
icon
4

Increased from to 4

Description

NIPA1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). Rainier et al., 2003 had previously determined that NIPA1 is highly expressed in neuronal tissues. A rare maternally-inherited missense variant in NIPA1 was observed in a male patient with ASD and speech delay in Brett et al., 2014; however, in silico analysis predicted that this variant was likely benign in effect. Heterozygous variants in the NIPA1 gene are also associated with a form of autosomal dominant spastic paraplegia (SPG6; OMIM 600363) (Rainier et al., 2003; Reed et al., 2005).

Reports Added
[NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6).2003] [A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.2005]
Krishnan Probability Score

Score 0.49259255706268

Ranking 4480/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.21409749585235

Ranking 6973/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92599865589116

Ranking 10335/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 0

Ranking 451/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.095682977075518

Ranking 6228/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with NIPA1(1 CNVs)
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15q11.2 122 Deletion-Duplication 161  /  2259
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