15-22786671-TGCGGCA-T

Variant summary

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

The NM_144599.5(NIPA1):c.21_26del(p.Ala15_Ala16del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000835 in 1,065,976 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: NIPA1 NM_144599.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.80

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 15-22786671-TGCGGCA-T is Benign according to our data. Variant chr15-22786671-TGCGGCA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 948284.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.21_26del	p.Ala15_Ala16del	inframe_deletion	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+429_-48+434del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.21_26del	p.Ala15_Ala16del	inframe_deletion	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12364_-48+12369del		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+429_-48+434del		intron_variant		1
NIPA1	ENST00000560069.5	n.31+429_31+434del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000324 AC: 45 AN: 138958 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000732

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000517

GnomAD3 exomes AF: 0.0000887 AC: 1 AN: 11276 Hom.: 0 AF XY: 0.000149 AC XY: 1 AN XY: 6724

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: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000475 AC: 44 AN: 926926 Hom.: 1 AF XY: 0.0000406 AC XY: 18 AN XY: 443670

Gnomad4 AFR exome AF: 0.000797

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000342

Gnomad4 SAS exome AF: 0.0000883

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.0000918

GnomAD4 genome AF: 0.000324 AC: 45 AN: 139050 Hom.: 0 Cov.: 27 AF XY: 0.000326 AC XY: 22 AN XY: 67480

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.0000731

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00161

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000511

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This variant, c.21_26del, results in the deletion of 2 amino acid(s) of the NIPA1 protein (p.Ala15_Ala16del), 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. This variant has been observed in at least one individual who was not affected with NIPA1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 948284). 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. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2021

- -

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: rs1555371600; hg19: chr15-23086397;