chr15-22786677-A-AGCGGCGGCG

Variant names:

• chr15-22786677-A-AGCGGCGGCG
• rs531550505
• NM_144599.5:c.39_47dupGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_144599.5(NIPA1):​c.39_47dupGGCGGCGGC​(p.Ala14_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 0.00021 (0 hom., cov: 6)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786677-A-AGCGGCGGCG is Benign according to our data. Variant chr15-22786677-A-AGCGGCGGCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.39_47dupGGCGGCGGC	p.Ala14_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+447_-48+455dupGGCGGCGGC		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.39_47dupGGCGGCGGC	p.Ala14_Ala16dup	disruptive_inframe_insertion	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 30 AN: 145406 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.000150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000338

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.000414

Gnomad SAS AF: 0.000850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000183

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000218 AC: 202 AN: 926066 Hom.: 0 Cov.: 3 AF XY: 0.000228 AC XY: 101 AN XY: 442810

Gnomad4 AFR exome AF: 0.000172

Gnomad4 AMR exome AF: 0.000342

Gnomad4 ASJ exome AF: 0.000367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000138

Gnomad4 FIN exome AF: 0.000125

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000206 AC: 30 AN: 145488 Hom.: 0 Cov.: 6 AF XY: 0.000170 AC XY: 12 AN XY: 70786

Gnomad4 AFR AF: 0.000149

Gnomad4 AMR AF: 0.000338

Gnomad4 ASJ AF: 0.000296

Gnomad4 EAS AF: 0.000415

Gnomad4 SAS AF: 0.000851

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000183

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 6 Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.39_47dup, results in the insertion of 3 amino acid(s) of the NIPA1 protein (p.Ala14_Ala16dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NIPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533362). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Jan 19, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 07, 2020

GeneDx

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;