15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCG

Position:

• chr15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCG

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_144599.5(NIPA1):​c.39_47del​(p.Ala14_Ala16del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,071,494 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 6)
  • Exomes 𝑓: 0.0018 (8 hom.)
• Consequence: NIPA1 NM_144599.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786677-AGCGGCGGCG-A is Benign according to our data. Variant chr15-22786677-AGCGGCGGCG-A is described in ClinVar as [Likely_benign]. Clinvar id is 241881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.39_47del	p.Ala14_Ala16del	inframe_deletion	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+447_-48+455del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.39_47del	p.Ala14_Ala16del	inframe_deletion	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12382_-48+12390del		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+447_-48+455del		intron_variant		1
NIPA1	ENST00000560069.5	n.31+447_31+455del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 201 AN: 145406 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.000399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000406

Gnomad ASJ AF: 0.00650

Gnomad EAS AF: 0.00476

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00306

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00149

GnomAD3 exomes AF: 0.000743 AC: 15 AN: 20176 Hom.: 0 AF XY: 0.000948 AC XY: 12 AN XY: 12652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000453

Gnomad ASJ exome AF: 0.00171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000638

Gnomad FIN exome AF: 0.000550

Gnomad NFE exome AF: 0.000682

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00177 AC: 1635 AN: 926006 Hom.: 8 AF XY: 0.00182 AC XY: 806 AN XY: 442788

Gnomad4 AFR exome AF: 0.000745

Gnomad4 AMR exome AF: 0.000342

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.000871

Gnomad4 FIN exome AF: 0.00424

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00138 AC: 201 AN: 145488 Hom.: 0 Cov.: 6 AF XY: 0.00130 AC XY: 92 AN XY: 70786

Gnomad4 AFR AF: 0.000398

Gnomad4 AMR AF: 0.000406

Gnomad4 ASJ AF: 0.00650

Gnomad4 EAS AF: 0.00478

Gnomad4 SAS AF: 0.000426

Gnomad4 FIN AF: 0.00306

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	NIPA1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	This variant is associated with the following publications: (PMID: 24866401) -

Hereditary spastic paraplegia 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs531550505; hg19: chr15-23086391;