rs11263683

Positions:

• chr15-22820436-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144599.5(NIPA1):​c.441A>G​(p.Thr147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,611,202 control chromosomes in the GnomAD database, including 431,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35508 hom., cov: 32)
  • Exomes 𝑓: 0.73 (396328 hom.)
• Consequence: NIPA1 NM_144599.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.55

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-22820436-A-G is Benign according to our data. Variant chr15-22820436-A-G is described in ClinVar as [Benign]. Clinvar id is 129804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-22820436-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.441A>G	p.Thr147=	synonymous_variant	4/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.216A>G	p.Thr72=	synonymous_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.441A>G	p.Thr147=	synonymous_variant	4/5	1	NM_144599.5	P1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101976 AN: 151912 Hom.: 35486 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.697

GnomAD3 exomes AF: 0.745 AC: 187314 AN: 251454 Hom.: 71106 AF XY: 0.749 AC XY: 101781 AN XY: 135902

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.866

Gnomad ASJ exome AF: 0.794

Gnomad EAS exome AF: 0.819

Gnomad SAS exome AF: 0.845

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.734 AC: 1071301 AN: 1459172 Hom.: 396328 Cov.: 39 AF XY: 0.738 AC XY: 535601 AN XY: 726056

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.859

Gnomad4 ASJ exome AF: 0.793

Gnomad4 EAS exome AF: 0.789

Gnomad4 SAS exome AF: 0.847

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.736

GnomAD4 genome AF: 0.671 AC: 102037 AN: 152030 Hom.: 35508 Cov.: 32 AF XY: 0.672 AC XY: 49963 AN XY: 74318

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.860

Gnomad4 FIN AF: 0.643

Gnomad4 NFE AF: 0.727

Gnomad4 OTH AF: 0.699

Alfa AF: 0.723 Hom.: 72568

Bravo AF: 0.675

Asia WGS AF: 0.811 AC: 2823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 22, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary spastic paraplegia 6 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.73
DANN	Benign	0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11263683; hg19: chr15-23052632; COSMIC: COSV61680320;