15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

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.39_47dupGGCGGCGGC(p.Ala14_Ala16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 6)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

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-A-AGCGGCGGCG is Benign according to our data. Variant chr15-22786677-A-AGCGGCGGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533362.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.39_47dupGGCGGCGGC	p.Ala14_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1 link	c.-48+447_-48+455dupGGCGGCGGC		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.39_47dupGGCGGCGGC	p.Ala14_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

145406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000338

Gnomad ASJ

AF:

0.000296

Gnomad EAS

AF:

0.000414

Gnomad SAS

AF:

0.000850

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000183

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000218

AC:

202

AN:

926066

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

101

AN XY:

442810

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

17460

American (AMR)

AF:

0.000342

AC:

AN:

5856

Ashkenazi Jewish (ASJ)

AF:

0.000367

AC:

AN:

8166

East Asian (EAS)

AF:

0.00

AC:

AN:

8916

South Asian (SAS)

AF:

0.000138

AC:

AN:

21810

European-Finnish (FIN)

AF:

0.000125

AC:

AN:

8024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2626

European-Non Finnish (NFE)

AF:

0.000225

AC:

185

AN:

820578

Other (OTH)

AF:

0.000153

AC:

AN:

32630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.000206

AC:

AN:

145488

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

70786

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

40200

American (AMR)

AF:

0.000338

AC:

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.000296

AC:

AN:

3384

East Asian (EAS)

AF:

0.000415

AC:

AN:

4816

South Asian (SAS)

AF:

0.000851

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:

0.000183

AC:

AN:

65558

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 6

Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.39_47dup, results in the insertion of 3 amino acid(s) of the NIPA1 protein (p.Ala14_Ala16dup), 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 poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NIPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533362). 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. -

not specified

Benign:1

Jan 19, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Apr 07, 2020

GeneDx

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