15-22786663-ACTGCAG-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_144599.5(NIPA1):c.12_17del(p.Ala15_Ala16del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000246 in 1,058,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NIPA1 NM_144599.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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 Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_144599.5.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.12_17del	p.Ala15_Ala16del	inframe_deletion	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+420_-48+425del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.12_17del	p.Ala15_Ala16del	inframe_deletion	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12355_-48+12360del		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+420_-48+425del		intron_variant		1
NIPA1	ENST00000560069.5	n.31+420_31+425del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000625 AC: 9 AN: 143924 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000609

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 17 AN: 914624 Hom.: 0 AF XY: 0.0000206 AC XY: 9 AN XY: 437724

Gnomad4 AFR exome AF: 0.000116

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000173

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000625 AC: 9 AN: 144024 Hom.: 0 Cov.: 30 AF XY: 0.0000999 AC XY: 7 AN XY: 70044

Gnomad4 AFR AF: 0.0000508

Gnomad4 AMR AF: 0.000138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000216

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000609

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2023

This variant, c.12_17del, results in the deletion of 2 amino acid(s) of the NIPA1 protein (p.Ala15_Ala16del), 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. This variant has been observed in at least one individual who was not affected with NIPA1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 639570). 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. -

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: rs1192699698; hg19: chr15-23086405;