chr15-22820436-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144599.5(NIPA1):c.441A>G(p.Thr147Thr) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.55

Publications

25 publications found

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]

NIPA1 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 6
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

NIPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.441A>G	p.Thr147Thr	synonymous_variant	Exon 4 of 5	ENST00000337435.9	NP_653200.2	Q7RTP0-1
NIPA1	NM_001142275.1 link	c.216A>G	p.Thr72Thr	synonymous_variant	Exon 4 of 5		NP_001135747.1	Q7RTP0-2A0A024R344Q8TAY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9 link	c.441A>G	p.Thr147Thr	synonymous_variant	Exon 4 of 5	1	NM_144599.5	ENSP00000337452.4		Q7RTP0-1

Frequencies

GnomAD3 genomes

AF:

0.671

AC:

101976

AN:

151912

Hom.:

35486

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.745

AC:

187314

AN:

251454

AF XY:

0.749

show subpopulations

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 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.:

AF XY:

0.738

AC XY:

535601

AN XY:

726056

show subpopulations

African (AFR)

AF:

0.479

AC:

16029

AN:

33442

American (AMR)

AF:

0.859

AC:

38411

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.793

AC:

20706

AN:

26126

East Asian (EAS)

AF:

0.789

AC:

31301

AN:

39696

South Asian (SAS)

AF:

0.847

AC:

73047

AN:

86212

European-Finnish (FIN)

AF:

0.637

AC:

34027

AN:

53400

Middle Eastern (MID)

AF:

0.726

AC:

4185

AN:

5764

European-Non Finnish (NFE)

AF:

0.729

AC:

809190

AN:

1109516

Other (OTH)

AF:

0.736

AC:

44405

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13974

27948

41923

55897

69871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20024

40048

60072

80096

100120

<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:

0.671

AC:

102037

AN:

152030

Hom.:

35508

Cov.:

AF XY:

0.672

AC XY:

49963

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.489

AC:

20261

AN:

41440

American (AMR)

AF:

0.793

AC:

12122

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.781

AC:

2712

AN:

3472

East Asian (EAS)

AF:

0.807

AC:

4159

AN:

5154

South Asian (SAS)

AF:

0.860

AC:

4149

AN:

4826

European-Finnish (FIN)

AF:

0.643

AC:

6789

AN:

10566

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.727

AC:

49424

AN:

67966

Other (OTH)

AF:

0.699

AC:

1478

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1571

3142

4713

6284

7855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<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:

0.715

Hom.:

150169

Bravo

AF:

0.675

Asia WGS

AF:

0.811

AC:

2823

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 05, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jan 21, 2016

GeneDx

Significance: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. -

Hereditary spastic paraplegia 6

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.73

(source)

DANN

Benign

0.42

PhyloP100

-5.6

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over