15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Position:

• chr15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3

The NM_144599.5(NIPA1):​c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC​(p.Ala4_Ala16dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as risk factor (★).

• Frequency: Genomes: not found (cov: 6)
• Consequence: NIPA1 NM_144599.5 inframe_insertion
• Clinical Significance: risk factor criteria provided, single submitter O:1
• 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 Likely_benign. Variant got -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala4_Ala16dup	inframe_insertion	1/5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+455_-48+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron_variant			NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala4_Ala16dup	inframe_insertion	1/5	1	NM_144599.5	ENSP00000337452	P1
NIPA1	ENST00000437912.6	c.-48+12390_-48+12391insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron_variant		1		ENSP00000393962
NIPA1	ENST00000561183.5	c.-48+455_-48+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron_variant		1		ENSP00000453722
NIPA1	ENST00000560069.5	n.31+455_31+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD4 exome Cov.: 3

GnomAD4 genome Cov.: 6

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis Other:1

risk factor, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Jul 31, 2020

Tazelaar et al. 2019 showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length -

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;