chr15-22786790-C-A

Variant names:

Variant summary

Our verdict is The variant received 4 classification points (ACMG Germline Pathogenicity v2019): 4P and 0B. PM2PM5

The NM_144599.5(NIPA1):c.134C>A (p.Thr45Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (AlphaMissense) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Uncertain Significance (★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T45R: Pathogenic (ClinVar VariationId 2520, 2 stars)

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NIPA1
NM_144599.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

NIPA1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_144599.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 points.

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

PM5

Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.T45R: Pathogenic (ClinVar VariationId 2520, 2 stars)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.134C>A	p.Thr45Lys	missense	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+542C>A		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.134C>A	p.Thr45Lys	missense	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
NIPA1	ENST00000437912.6	TSL:1	c.-48+12477C>A		intron	N/A	ENSP00000393962.2	Q7RTP0-2
NIPA1	ENST00000561183.5	TSL:1	c.-48+542C>A		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1155566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

573050

African (AFR)

AF:

0.00

AC:

AN:

23600

American (AMR)

AF:

0.00

AC:

AN:

29144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16138

East Asian (EAS)

AF:

0.00

AC:

AN:

16038

South Asian (SAS)

AF:

0.00

AC:

AN:

63092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4380

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

937220

Other (OTH)

AF:

0.00

AC:

AN:

42122

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

LIST_S2

Benign

0.78

MetaRNN

Uncertain

0.65

PhyloP100

1.1

PROVEAN

Benign

-1.7

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

PromoterAI

-0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.99

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over