15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_144599.5(NIPA1):c.45_47dupGGC(p.Ala16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 6)

Exomes 𝑓: 0.0061 ( 29 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

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: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_144599.5

BP6

Variant 15-22786677-A-AGCG is Benign according to our data. Variant chr15-22786677-A-AGCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00631 (918/145480) while in subpopulation SAS AF = 0.0245 (115/4694). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 6. This position passed quality control check.

BS2

High AC in GnomAd4 at 918 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.45_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1 link	c.-48+453_-48+455dupGGC		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.45_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

918

AN:

145398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00517

Gnomad SAS

AF:

0.0245

Gnomad FIN

AF:

0.00136

Gnomad MID

AF:

0.0164

Gnomad NFE

AF:

0.00531

Gnomad OTH

AF:

0.00397

GnomAD2 exomes

AF:

0.00139

AC:

AN:

20176

AF XY:

0.00126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00317

Gnomad ASJ exome

AF:

0.00683

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000568

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00608

AC:

5626

AN:

925778

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

2691

AN XY:

442652

show subpopulations

African (AFR)

AF:

0.00556

AC:

AN:

17456

American (AMR)

AF:

0.00291

AC:

AN:

5850

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

137

AN:

8162

East Asian (EAS)

AF:

0.00348

AC:

AN:

8912

South Asian (SAS)

AF:

0.0211

AC:

460

AN:

21782

European-Finnish (FIN)

AF:

0.000748

AC:

AN:

8022

Middle Eastern (MID)

AF:

0.00343

AC:

AN:

2626

European-Non Finnish (NFE)

AF:

0.00556

AC:

4562

AN:

820354

Other (OTH)

AF:

0.00941

AC:

307

AN:

32614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.00631

AC:

918

AN:

145480

Hom.:

Cov.:

AF XY:

0.00647

AC XY:

458

AN XY:

70780

show subpopulations

African (AFR)

AF:

0.00600

AC:

241

AN:

40200

American (AMR)

AF:

0.00609

AC:

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3384

East Asian (EAS)

AF:

0.00519

AC:

AN:

4816

South Asian (SAS)

AF:

0.0245

AC:

115

AN:

4694

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

8836

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00531

AC:

348

AN:

65554

Other (OTH)

AF:

0.00394

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000538

Hom.:

108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NIPA1: BS1, BS2 -

Dec 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 6

Benign:2

Jul 05, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in homozygous state. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 10, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Aug 17, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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