chr15-22786677-A-AGCG

Variant names:

• chr15-22786677-A-AGCG
• rs531550505
• NM_144599.5:c.45_47dupGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_144599.5(NIPA1):​c.45_47dupGGC​(p.Ala16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 6)
  • Exomes 𝑓: 0.0061 (29 hom.)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786677-A-AGCG is Benign according to our data. Variant chr15-22786677-A-AGCG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00631 (918/145480) while in subpopulation SAS AF = 0.0245 (115/4694). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 6. This position passed quality control check.
• BS2: High AC in GnomAd4 at 918 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.45_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+453_-48+455dupGGC		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_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12388_-48+12390dupGGC		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+453_-48+455dupGGC		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 918 AN: 145398 Hom.: 5 Cov.: 6

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00517

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.00136

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00397

GnomAD2 exomes AF: 0.00139 AC: 28 AN: 20176 AF XY: 0.00126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.00683

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00608 AC: 5626 AN: 925778 Hom.: 29 Cov.: 3 AF XY: 0.00608 AC XY: 2691 AN XY: 442652

African (AFR) AF: 0.00556 AC: 97 AN: 17456

American (AMR) AF: 0.00291 AC: 17 AN: 5850

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 137 AN: 8162

East Asian (EAS) AF: 0.00348 AC: 31 AN: 8912

South Asian (SAS) AF: 0.0211 AC: 460 AN: 21782

European-Finnish (FIN) AF: 0.000748 AC: 6 AN: 8022

Middle Eastern (MID) AF: 0.00343 AC: 9 AN: 2626

European-Non Finnish (NFE) AF: 0.00556 AC: 4562 AN: 820354

Other (OTH) AF: 0.00941 AC: 307 AN: 32614

GnomAD4 genome AF: 0.00631 AC: 918 AN: 145480 Hom.: 5 Cov.: 6 AF XY: 0.00647 AC XY: 458 AN XY: 70780

African (AFR) AF: 0.00600 AC: 241 AN: 40200

American (AMR) AF: 0.00609 AC: 90 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 74 AN: 3384

East Asian (EAS) AF: 0.00519 AC: 25 AN: 4816

South Asian (SAS) AF: 0.0245 AC: 115 AN: 4694

European-Finnish (FIN) AF: 0.00136 AC: 12 AN: 8836

Middle Eastern (MID) AF: 0.0177 AC: 5 AN: 282

European-Non Finnish (NFE) AF: 0.00531 AC: 348 AN: 65554

Other (OTH) AF: 0.00394 AC: 8 AN: 2030

Alfa AF: 0.000538 Hom.: 108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 6 (2)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (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;