chr15-22786677-AGCG-A

Position:

• chr15-22786677-AGCG-A

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 193495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-22786677-AGCG-A is described in Lovd as [Benign]. Variant chr15-22786677-AGCG-A is described in Lovd as [Likely_benign]. Variant chr15-22786677-AGCG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.45_47delGGC	p.Ala16del	disruptive_inframe_deletion	1/5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+453_-48+455delGGC		intron_variant			NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.45_47delGGC	p.Ala16del	disruptive_inframe_deletion	1/5	1	NM_144599.5	ENSP00000337452.4
NIPA1	ENST00000437912.6	c.-48+12388_-48+12390delGGC		intron_variant		1		ENSP00000393962.2
NIPA1	ENST00000561183.5	c.-48+453_-48+455delGGC		intron_variant		1		ENSP00000453722.1
NIPA1	ENST00000560069.5	n.31+453_31+455delGGC		intron_variant		4

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

GnomAD3 exomes AF: 0.0789 AC: 1592 AN: 20176 Hom.: 182 AF XY: 0.0696 AC XY: 880 AN XY: 12652

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 SAS exome AF: 0.0460

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

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.224

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

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.437

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.267

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Spastic paraplegia, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spastic paraplegia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs531550505; hg19: chr15-23086391;