15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chr15-22786677-A-AGCGGCG
• rs531550505
• NM_144599.5:c.42_47dupGGCGGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_144599.5(NIPA1):​c.42_47dupGGCGGC​(p.Ala15_Ala16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (17 hom., cov: 6)
  • Exomes 𝑓: 0.014 (86 hom.)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786677-A-AGCGGCG is Benign according to our data. Variant chr15-22786677-A-AGCGGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193496.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0141 (2047/145470) while in subpopulation NFE AF = 0.0172 (1125/65550). AF 95% confidence interval is 0.0163. There are 17 homozygotes in GnomAd4. There are 952 alleles in the male GnomAd4 subpopulation. Median coverage is 6. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2047 AD gene.

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.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+450_-48+455dupGGCGGC		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.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12385_-48+12390dupGGCGGC		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+450_-48+455dupGGCGGC		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2045 AN: 145388 Hom.: 17 Cov.: 6

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0436

Gnomad AMR AF: 0.00663

Gnomad ASJ AF: 0.00946

Gnomad EAS AF: 0.00393

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00600

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0114

GnomAD2 exomes AF: 0.000297 AC: 6 AN: 20176 AF XY: 0.000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000550

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0143 AC: 13245 AN: 925310 Hom.: 86 Cov.: 3 AF XY: 0.0144 AC XY: 6367 AN XY: 442450

African (AFR) AF: 0.0121 AC: 211 AN: 17444

American (AMR) AF: 0.00325 AC: 19 AN: 5854

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 73 AN: 8152

East Asian (EAS) AF: 0.00270 AC: 24 AN: 8904

South Asian (SAS) AF: 0.0115 AC: 251 AN: 21798

European-Finnish (FIN) AF: 0.00611 AC: 49 AN: 8016

Middle Eastern (MID) AF: 0.0148 AC: 39 AN: 2628

European-Non Finnish (NFE) AF: 0.0149 AC: 12183 AN: 819910

Other (OTH) AF: 0.0121 AC: 396 AN: 32604

GnomAD4 genome AF: 0.0141 AC: 2047 AN: 145470 Hom.: 17 Cov.: 6 AF XY: 0.0135 AC XY: 952 AN XY: 70776

African (AFR) AF: 0.0146 AC: 587 AN: 40196

American (AMR) AF: 0.00663 AC: 98 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.00946 AC: 32 AN: 3382

East Asian (EAS) AF: 0.00395 AC: 19 AN: 4816

South Asian (SAS) AF: 0.0149 AC: 70 AN: 4696

European-Finnish (FIN) AF: 0.00600 AC: 53 AN: 8834

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.0172 AC: 1125 AN: 65550

Other (OTH) AF: 0.0113 AC: 23 AN: 2030

Alfa AF: 0.00507 Hom.: 108

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

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;