15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCG

Position:

• chr15-22786677-AGCGGCGGCGGCGGCGGCGGCG-AGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Benign. Variant got -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:5
• 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]

ACMG classification

Verdict is Benign. Variant got -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 id is 193496.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=3}.
• 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 male gnomad4 subpopulation. Median coverage is 6. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2047 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	1/5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+450_-48+455dupGGCGGC		intron_variant			NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.42_47dupGGCGGC	p.Ala15_Ala16dup	disruptive_inframe_insertion	1/5	1	NM_144599.5	ENSP00000337452.4
NIPA1	ENST00000437912.6	c.-48+12385_-48+12390dupGGCGGC		intron_variant		1		ENSP00000393962.2
NIPA1	ENST00000561183.5	c.-48+450_-48+455dupGGCGGC		intron_variant		1		ENSP00000453722.1
NIPA1	ENST00000560069.5	n.31+450_31+455dupGGCGGC		intron_variant		4

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

GnomAD3 exomes AF: 0.000297 AC: 6 AN: 20176 Hom.: 0 AF XY: 0.000237 AC XY: 3 AN XY: 12652

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 SAS 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

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.00325

Gnomad4 ASJ exome AF: 0.00895

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00611

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0121

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

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.00663

Gnomad4 ASJ AF: 0.00946

Gnomad4 EAS AF: 0.00395

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00600

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 13, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 23, 2015

- -

Spastic paraplegia, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2020

Not observed in large population cohorts (Lek et al., 2016) -

Hereditary spastic paraplegia 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;