rs1356799862

Variant names:

• chr15-22812235-C-A
• rs1356799862
• NM_144599.5:c.299C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-22812235-C-A
• chr15-22812235-C-G
• chr15-22812235-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_144599.5(NIPA1):​c.299C>A​(p.Ala100Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A100T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 6

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_144599.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144599.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.299C>A	p.Ala100Asp	missense	Exon 3 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.74C>A	p.Ala25Asp	missense	Exon 3 of 5	NP_001135747.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.299C>A	p.Ala100Asp	missense	Exon 3 of 5	ENSP00000337452.4
	NIPA1	ENST00000437912.6	TSL:1	c.74C>A	p.Ala25Asp	missense	Exon 3 of 5	ENSP00000393962.2
	NIPA1	ENST00000561183.5	TSL:1	c.74C>A	p.Ala25Asp	missense	Exon 3 of 5	ENSP00000453722.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.90	D
PhyloP100		5.9
PROVEAN	Pathogenic	-5.6	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		1.0

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

Other links and lift over

dbSNP: rs1356799862; hg19: chr15-23060833;