chr15-22786677-A-AGCG

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 6. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 918 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.45_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+453_-48+455dupGGC		intron_variant	Intron 1 of 4		NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.45_47dupGGC	p.Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

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

GnomAD3 exomes AF: 0.00139 AC: 28 AN: 20176 Hom.: 0 AF XY: 0.00126 AC XY: 16 AN XY: 12652

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 SAS exome AF: 0.000851

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

Gnomad4 AFR exome AF: 0.00556

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.00348

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.000748

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00941

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

Gnomad4 AFR AF: 0.00600

Gnomad4 AMR AF: 0.00609

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00519

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.00136

Gnomad4 NFE AF: 0.00531

Gnomad4 OTH AF: 0.00394

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NIPA1: BS1, BS2 -

Dec 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 6 Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in homozygous state. -

not specified Benign:1

Apr 10, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Aug 17, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;