15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_144599.5(NIPA1):c.36_47delGGCGGCGGCGGC(p.Ala13_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 0.000136 in 1,071,552 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 6)

Exomes 𝑓: 0.00014 ( 4 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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 -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_144599.5

BP6

Variant 15-22786677-AGCGGCGGCGGCG-A is Benign according to our data. Variant chr15-22786677-AGCGGCGGCGGCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 872110.

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.36_47delGGCGGCGGCGGC	p.Ala13_Ala16del	disruptive_inframe_deletion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1 link	c.-48+444_-48+455delGGCGGCGGCGGC		intron_variant	Intron 1 of 4		NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9 link	c.36_47delGGCGGCGGCGGC	p.Ala13_Ala16del	disruptive_inframe_deletion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

145406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000425

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000915

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

129

AN:

926064

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

442810

show subpopulations

African (AFR)

AF:

0.000115

AC:

AN:

17460

American (AMR)

AF:

0.000171

AC:

AN:

5852

Ashkenazi Jewish (ASJ)

AF:

0.000122

AC:

AN:

8164

East Asian (EAS)

AF:

0.00

AC:

AN:

8916

South Asian (SAS)

AF:

0.000367

AC:

AN:

21806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2628

European-Non Finnish (NFE)

AF:

0.000135

AC:

111

AN:

820586

Other (OTH)

AF:

0.000184

AC:

AN:

32630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000117

AC:

AN:

145488

Hom.:

Cov.:

AF XY:

0.0000848

AC XY:

AN XY:

70786

show subpopulations

African (AFR)

AF:

0.000224

AC:

AN:

40200

American (AMR)

AF:

0.00

AC:

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4816

South Asian (SAS)

AF:

0.000426

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:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 6

Uncertain:1

Apr 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.36_47del, results in the deletion of 4 amino acid(s) of the NIPA1 protein (p.Ala13_Ala16del), but otherwise preserves the integrity of the reading frame. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with NIPA1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

not provided

Benign:1

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over