Genetic Variant NIPA1:p.Ala8_Ala9del (chr15-22786671-TGCGGCA-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_144599.5(NIPA1):c.21_26delAGCGGC(p.Ala8_Ala9del) variant causes a disruptive 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

NIPA1
NM_144599.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.80

Publications

0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

NIPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 Benign/Likely_benign. ClinVar VariationId is 948284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 45 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144599.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.21_26delAGCGGC	p.Ala8_Ala9del	disruptive_inframe_deletion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+429_-48+434delAGCGGC		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.21_26delAGCGGC	p.Ala8_Ala9del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
NIPA1	ENST00000437912.6	TSL:1	c.-48+12364_-48+12369delAGCGGC		intron	N/A	ENSP00000393962.2	Q7RTP0-2
NIPA1	ENST00000561183.5	TSL:1	c.-48+429_-48+434delAGCGGC		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

138958

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000887

AC:

AN:

11276

AF XY:

0.000149

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000475

AC:

AN:

926926

Hom.:

AF XY:

0.0000406

AC XY:

AN XY:

443670

show subpopulations

African (AFR)

AF:

0.000797

AC:

AN:

17564

American (AMR)

AF:

0.00

AC:

AN:

6766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8322

East Asian (EAS)

AF:

0.000342

AC:

AN:

8778

South Asian (SAS)

AF:

0.0000883

AC:

AN:

22656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2652

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

819278

Other (OTH)

AF:

0.0000918

AC:

AN:

32680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000324

AC:

AN:

139050

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

AN XY:

67480

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

37422

American (AMR)

AF:

0.0000731

AC:

AN:

13684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3314

East Asian (EAS)

AF:

0.00161

AC:

AN:

4354

South Asian (SAS)

AF:

0.00

AC:

AN:

4506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64228

Other (OTH)

AF:

0.000511

AC:

AN:

1958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over