15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCG

Variant names:

• chr15-22786677-AGCG-A
• rs531550505
• NM_144599.5:c.45_47delGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_144599.5(NIPA1):​c.45_47delGGC​(p.Ala16del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,049,866 control chromosomes in the GnomAD database, including 24,726 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5263 hom., cov: 6)
  • Exomes 𝑓: 0.22 (19463 hom.)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786677-AGCG-A is Benign according to our data. Variant chr15-22786677-AGCG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.45_47delGGC	p.Ala16del	disruptive_inframe_deletion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+453_-48+455delGGC		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.45_47delGGC	p.Ala16del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12388_-48+12390delGGC		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+453_-48+455delGGC		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 37911 AN: 145188 Hom.: 5258 Cov.: 6

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.0789 AC: 1592 AN: 20176 AF XY: 0.0696

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.0695

Gnomad EAS exome AF: 0.0500

Gnomad FIN exome AF: 0.0589

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0749

GnomAD4 exome AF: 0.220 AC: 198910 AN: 904596 Hom.: 19463 AF XY: 0.221 AC XY: 95281 AN XY: 431928

African (AFR) AF: 0.329 AC: 5641 AN: 17134

American (AMR) AF: 0.367 AC: 2079 AN: 5666

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 1755 AN: 7916

East Asian (EAS) AF: 0.424 AC: 3690 AN: 8708

South Asian (SAS) AF: 0.194 AC: 4106 AN: 21212

European-Finnish (FIN) AF: 0.282 AC: 2207 AN: 7816

Middle Eastern (MID) AF: 0.152 AC: 390 AN: 2566

European-Non Finnish (NFE) AF: 0.214 AC: 171926 AN: 801752

Other (OTH) AF: 0.224 AC: 7116 AN: 31826

GnomAD4 genome AF: 0.261 AC: 37940 AN: 145270 Hom.: 5263 Cov.: 6 AF XY: 0.266 AC XY: 18829 AN XY: 70680

African (AFR) AF: 0.322 AC: 12902 AN: 40130

American (AMR) AF: 0.316 AC: 4666 AN: 14762

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 723 AN: 3382

East Asian (EAS) AF: 0.437 AC: 2097 AN: 4802

South Asian (SAS) AF: 0.191 AC: 894 AN: 4688

European-Finnish (FIN) AF: 0.267 AC: 2358 AN: 8818

Middle Eastern (MID) AF: 0.121 AC: 34 AN: 282

European-Non Finnish (NFE) AF: 0.208 AC: 13645 AN: 65488

Other (OTH) AF: 0.229 AC: 464 AN: 2024

Alfa AF: 0.0749 Hom.: 108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 6 (1)
-	-	1	Spastic paraplegia, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs531550505; hg19: chr15-23086391; COSMIC: COSV61679565; COSMIC: COSV61679565;