rs104894496

Positions:

• chr15-22786790-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_144599.5(NIPA1):​c.134C>G​(p.Thr45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.08

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]

NIPA1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-22786790-C-G is Pathogenic according to our data. Variant chr15-22786790-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-22786790-C-G is described in UniProt as null. Variant chr15-22786790-C-G is described in UniProt as null. Variant chr15-22786790-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.134C>G	p.Thr45Arg	missense_variant	1/5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+542C>G		intron_variant			NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.134C>G	p.Thr45Arg	missense_variant	1/5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 6 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the NIPA1 protein (p.Thr45Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 14508710). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2520). 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, 20816793). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2023

Published functional studies demonstrate a damaging effect and show that this variant affects normal protein function and has profound effects on cellular distributions (Goytain et al., 2007; Botzolakis et al., 2011); 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: 18191948, 19091982, 35181192, 35464835, 19620182, 22302102, 32384786, 22552817, 20816793, 17166836, 14508710) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
LIST_S2	Benign	0.81	T
MetaRNN	Uncertain	0.53	D
PROVEAN	Uncertain	-2.4	N
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.47
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894496; hg19: chr15-23086278;