chr15-22786673-C-A

Variant names:

• chr15-22786673-C-A
• rs944860201
• NM_144599.5:c.17C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144599.5(NIPA1):​c.17C>A​(p.Ala6Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13440615).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.17C>A	p.Ala6Glu	missense	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+425C>A		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.17C>A	p.Ala6Glu	missense	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12360C>A		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+425C>A		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 939122 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 449314

African (AFR) AF: 0.00 AC: 0 AN: 17736

American (AMR) AF: 0.00 AC: 0 AN: 6768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8390

East Asian (EAS) AF: 0.00 AC: 0 AN: 9038

South Asian (SAS) AF: 0.00 AC: 0 AN: 22724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 830146

Other (OTH) AF: 0.00 AC: 0 AN: 33110

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.047	T
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.13	T
PhyloP100		2.8
PROVEAN	Benign	0.78	N
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.21	T
Vest4		0.38
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
gMVP		0.75

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: rs944860201; hg19: chr15-23086395;