rs104894490

chr15-22812252-G-Achr15-22812252-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_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. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPA1 NM_144599.5 missense, splice_region
• Scores: Splicing: ADA: 0.9928
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• 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	UniProt
NIPA1	NM_144599.5	c.316G>A	p.Gly106Arg	missense_variant, splice_region_variant	3/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.91G>A	p.Gly31Arg	missense_variant, splice_region_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.316G>A	p.Gly106Arg	missense_variant, splice_region_variant	3/5	1	NM_144599.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452338 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 19, 2020	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant results in the same amino acid change as another variant considered to be pathogenic (c.316G>C). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant impairs magnesium transport and results in protein accumulation in the endoplasmic reticulum (PMID 17166836, 19091982, 20816793). Computational tools predict that this variant is damaging. -
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	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2021	PP1, PM2, PM6, PS1, PS3, PS4_moderate -

Hereditary spastic paraplegia 6 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
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	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Uncertain	1.0
MetaRNN	Pathogenic	0.86	D;D;D
PROVEAN	Benign	-1.9	N;N;N
Sift	Benign	0.035	D;D;D
Vest4		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894490; hg19: chr15-23060816; COSMIC: COSV105224418; COSMIC: COSV105224418;