15-22786677-A-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 11 publications found

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]

NIPA1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 6

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144599.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala16_Gly17insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+455_-48+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron	N/A	NP_001135747.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.47_48insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala16_Gly17insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000337452.4
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12390_-48+12391insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron	N/A	ENSP00000393962.2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+455_-48+456insGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC		intron	N/A	ENSP00000453722.1

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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

Other links and lift over

dbSNP: rs531550505; hg19: chr15-23086391;