15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr15-22786677-A-AGCGGCGGCGGCGGCGGCG
• rs531550505
• NM_144599.5:c.30_47dupGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_144599.5(NIPA1):​c.30_47dupGGCGGCGGCGGCGGCGGC​(p.Ala11_Ala16dup) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 6)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.30_47dupGGCGGCGGCGGCGGCGGC	p.Ala11_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+438_-48+455dupGGCGGCGGCGGCGGCGGC		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.30_47dupGGCGGCGGCGGCGGCGGC	p.Ala11_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes AF: 0.00000688 AC: 1 AN: 145406 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 3

GnomAD4 genome AF: 0.00000688 AC: 1 AN: 145406 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 70686

African (AFR) AF: 0.0000249 AC: 1 AN: 40094

American (AMR) AF: 0.00 AC: 0 AN: 14774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4834

South Asian (SAS) AF: 0.00 AC: 0 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65568

Other (OTH) AF: 0.00 AC: 0 AN: 2014

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;