15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr15-22786677-A-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG
• rs531550505
• NM_144599.5:c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

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.Ala16_Gly17insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla) variant causes a disruptive 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 disruptive_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 rank	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala16_Gly17insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+455_-48+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 4		NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala16_Gly17insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

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

Jul 31, 2020

UM ALS/MND Lab, University Of Malta

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: case-control

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;