15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCG

Position:

• chr15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCG

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.42_47del​(p.Ala15_Ala16del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,067,564 control chromosomes in the GnomAD database, including 4 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 0.0033 (3 hom., cov: 6)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: NIPA1 NM_144599.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-AGCGGCG-A is Benign according to our data. Variant chr15-22786677-AGCGGCG-A is described in ClinVar as [Likely_benign]. Clinvar id is 412532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-22786677-AGCGGCG-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 483 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.42_47del	p.Ala15_Ala16del	inframe_deletion	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+450_-48+455del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.42_47del	p.Ala15_Ala16del	inframe_deletion	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12385_-48+12390del		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+450_-48+455del		intron_variant		1
NIPA1	ENST00000560069.5	n.31+450_31+455del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 484 AN: 145394 Hom.: 3 Cov.: 6

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000621

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000347 AC: 7 AN: 20176 Hom.: 0 AF XY: 0.000316 AC XY: 4 AN XY: 12652

Gnomad AFR exome AF: 0.00485

Gnomad AMR exome AF: 0.000907

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00105 AC: 971 AN: 922088 Hom.: 1 AF XY: 0.00110 AC XY: 484 AN XY: 440864

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.00573

Gnomad4 ASJ exome AF: 0.000984

Gnomad4 EAS exome AF: 0.00216

Gnomad4 SAS exome AF: 0.00318

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.000694

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00332 AC: 483 AN: 145476 Hom.: 3 Cov.: 6 AF XY: 0.00325 AC XY: 230 AN XY: 70784

Gnomad4 AFR AF: 0.00995

Gnomad4 AMR AF: 0.00122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000623

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00197

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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	May 01, 2022	NIPA1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 01, 2018

- -

Hereditary spastic paraplegia 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 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;