15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_144599.5(NIPA1):c.33_47delGGCGGCGGCGGCGGC(p.Ala12_Ala16del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,071,576 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., cov: 6)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Publications

11 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

NIPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_144599.5

BS2

High AC in GnomAd4 at 12 AD gene.

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.33_47delGGCGGCGGCGGCGGC	p.Ala12_Ala16del	disruptive_inframe_deletion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+441_-48+455delGGCGGCGGCGGCGGC		intron	N/A	NP_001135747.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.33_47delGGCGGCGGCGGCGGC	p.Ala12_Ala16del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000337452.4
NIPA1	ENST00000437912.6	TSL:1	c.-48+12376_-48+12390delGGCGGCGGCGGCGGC		intron	N/A	ENSP00000393962.2
NIPA1	ENST00000561183.5	TSL:1	c.-48+441_-48+455delGGCGGCGGCGGCGGC		intron	N/A	ENSP00000453722.1

Frequencies

GnomAD3 genomes

AF:

0.0000757

AC:

AN:

145406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000621

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000915

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000659

AC:

AN:

926088

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

442824

show subpopulations

African (AFR)

AF:

0.0000573

AC:

AN:

17460

American (AMR)

AF:

0.00

AC:

AN:

5854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8166

East Asian (EAS)

AF:

0.00213

AC:

AN:

8916

South Asian (SAS)

AF:

0.000138

AC:

AN:

21810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8024

Middle Eastern (MID)

AF:

0.000761

AC:

AN:

2628

European-Non Finnish (NFE)

AF:

0.0000390

AC:

AN:

820598

Other (OTH)

AF:

0.000123

AC:

AN:

32632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000825

AC:

AN:

145488

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

70786

show subpopulations

African (AFR)

AF:

0.0000498

AC:

AN:

40200

American (AMR)

AF:

0.00

AC:

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.000623

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0000915

AC:

AN:

65558

Other (OTH)

AF:

0.000493

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

108

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 6

Uncertain:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.33_47del, results in the deletion of 5 amino acid(s) of the NIPA1 protein (p.Ala12_Ala16del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NIPA1-related conditions. This variant has been observed in at least one individual who was not affected with NIPA1-related conditions (internal data). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over