Genetic Variant NIPA1:p.Ala15_Ala16dup (chr15-22786677-A-AGCGGCG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_144599.5(NIPA1):c.42_47dupGGCGGC(p.Ala15_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 0.014 ( 17 hom., cov: 6)

Exomes 𝑓: 0.014 ( 86 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.48

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_144599.5

BP6

Variant 15-22786677-A-AGCGGCG is Benign according to our data. Variant chr15-22786677-A-AGCGGCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193496.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0141 (2047/145470) while in subpopulation NFE AF= 0.0172 (1125/65550). AF 95% confidence interval is 0.0163. There are 17 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 6. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2047 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2	Q7RTP0-1
NIPA1	NM_001142275.1 link	c.-48+450_-48+455dupGGCGGC		intron_variant	Intron 1 of 4		NP_001135747.1	Q7RTP0-2A0A024R344Q8TAY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9 link	c.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4		Q7RTP0-1

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2045

AN:

145388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0436

Gnomad AMR

AF:

0.00663

Gnomad ASJ

AF:

0.00946

Gnomad EAS

AF:

0.00393

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00600

Gnomad MID

AF:

0.00658

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0114

GnomAD3 exomes

AF:

0.000297

AC:

AN:

20176

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

12652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000550

Gnomad NFE exome

AF:

0.000568

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0143

AC:

13245

AN:

925310

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

6367

AN XY:

442450

show subpopulations

Gnomad4 AFR exome

AF:

0.0121

Gnomad4 AMR exome

AF:

0.00325

Gnomad4 ASJ exome

AF:

0.00895

Gnomad4 EAS exome

AF:

0.00270

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.00611

Gnomad4 NFE exome

AF:

0.0149

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.0141

AC:

2047

AN:

145470

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

952

AN XY:

70776

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.00663

Gnomad4 ASJ

AF:

0.00946

Gnomad4 EAS

AF:

0.00395

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.00600

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1Benign:1

Dec 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:1

Apr 23, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia, autosomal dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

May 07, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016) -

Hereditary spastic paraplegia 6

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over