15-22786674-GGCA-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_144599.5(NIPA1):c.21_23del(p.Ala16del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,074,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: NIPA1 NM_144599.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62

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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786674-GGCA-G is Benign according to our data. Variant chr15-22786674-GGCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 695853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.21_23del	p.Ala16del	inframe_deletion	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+429_-48+431del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.21_23del	p.Ala16del	inframe_deletion	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12364_-48+12366del		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+429_-48+431del		intron_variant		1
NIPA1	ENST00000560069.5	n.31+429_31+431del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 34 AN: 135802 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000150

Gnomad ASJ AF: 0.000308

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000369 AC: 4 AN: 10834 Hom.: 0 AF XY: 0.000311 AC XY: 2 AN XY: 6422

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: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 198 AN: 939078 Hom.: 0 AF XY: 0.000218 AC XY: 98 AN XY: 449476

Gnomad4 AFR exome AF: 0.000113

Gnomad4 AMR exome AF: 0.000147

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000110

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000211

GnomAD4 genome AF: 0.000250 AC: 34 AN: 135876 Hom.: 0 Cov.: 27 AF XY: 0.000288 AC XY: 19 AN XY: 65866

Gnomad4 AFR AF: 0.0000277

Gnomad4 AMR AF: 0.000150

Gnomad4 ASJ AF: 0.000308

Gnomad4 EAS AF: 0.000245

Gnomad4 SAS AF: 0.00334

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2022

- -

Hereditary spastic paraplegia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2023

- -

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: rs769916931; hg19: chr15-23086394;