chr15-22812248-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_144599.5(NIPA1):​c.312G>A​(p.Pro104Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,607,748 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0012 ( 5 hom. )

Consequence

NIPA1
NM_144599.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.100
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 15-22812248-G-A is Benign according to our data. Variant chr15-22812248-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289458.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr15-22812248-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.1 with no splicing effect.
BS2
High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NIPA1NM_144599.5 linkc.312G>A p.Pro104Pro synonymous_variant Exon 3 of 5 ENST00000337435.9 NP_653200.2 Q7RTP0-1
NIPA1NM_001142275.1 linkc.87G>A p.Pro29Pro synonymous_variant Exon 3 of 5 NP_001135747.1 Q7RTP0-2A0A024R344Q8TAY1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NIPA1ENST00000337435.9 linkc.312G>A p.Pro104Pro synonymous_variant Exon 3 of 5 1 NM_144599.5 ENSP00000337452.4 Q7RTP0-1

Frequencies

GnomAD3 genomes
AF:
0.000585
AC:
89
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00106
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000633
AC:
159
AN:
251228
AF XY:
0.000582
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000924
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00107
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.00121
AC:
1767
AN:
1455426
Hom.:
5
Cov.:
29
AF XY:
0.00119
AC XY:
864
AN XY:
724462
show subpopulations
Gnomad4 AFR exome
AF:
0.000390
AC:
13
AN:
33338
Gnomad4 AMR exome
AF:
0.000201
AC:
9
AN:
44698
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26088
Gnomad4 EAS exome
AF:
0.00119
AC:
47
AN:
39644
Gnomad4 SAS exome
AF:
0.0000348
AC:
3
AN:
86134
Gnomad4 FIN exome
AF:
0.0000375
AC:
2
AN:
53388
Gnomad4 NFE exome
AF:
0.00150
AC:
1656
AN:
1106206
Gnomad4 Remaining exome
AF:
0.000615
AC:
37
AN:
60178
Heterozygous variant carriers
0
76
152
227
303
379
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
72
144
216
288
360
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000584
AC:
89
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.000537
AC XY:
40
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.000265
AC:
0.000264614
AN:
0.000264614
Gnomad4 AMR
AF:
0.000131
AC:
0.000130736
AN:
0.000130736
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.000386
AC:
0.000385654
AN:
0.000385654
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.000188
AC:
0.000188359
AN:
0.000188359
Gnomad4 NFE
AF:
0.00106
AC:
0.00105829
AN:
0.00105829
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000846
Hom.:
0
Bravo
AF:
0.000552
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
-
Clinical Genetics, Academic Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 15, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary spastic paraplegia 6 Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Feb 13, 2017
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

NIPA1-related disorder Benign:1
Mar 05, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia Benign:1
Jul 01, 2018
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

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
CADD
Benign
3.0
DANN
Benign
0.77
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139372534; hg19: chr15-23060820; API