Genetic Variant NIPA1:c.-48+3344T>C (chr15-22777657-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000437912.6(NIPA1):c.-48+3344T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 151,902 control chromosomes in the GnomAD database, including 5,627 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5627 hom., cov: 32)

Exomes 𝑓: 0.20 ( 0 hom. )

Consequence

NIPA1
ENST00000437912.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.51

Publications

3 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:

ENSG00000274253 (HGNC:):

ENSG00000274253 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC283683	NR_040057.1 link	n.475-110T>C		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
NIPA1	ENST00000437912.6 link	c.-48+3344T>C	intron_variant	Intron 1 of 4	1	ENSP00000393962.2
ENSG00000274253	ENST00000619611.4 link	n.475-110T>C	intron_variant	Intron 4 of 4	1
ENSG00000274253	ENST00000716901.1 link	n.567-92T>C	intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39057

AN:

151774

Hom.:

5616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.335

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.493

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.124

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.227

GnomAD4 exome

AF:

0.200

AC:

AN:

Hom.:

AF XY:

0.200

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.257

AC:

39108

AN:

151892

Hom.:

5627

Cov.:

AF XY:

0.262

AC XY:

19445

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.335

AC:

13890

AN:

41444

American (AMR)

AF:

0.313

AC:

4770

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

738

AN:

3468

East Asian (EAS)

AF:

0.493

AC:

2512

AN:

5100

South Asian (SAS)

AF:

0.207

AC:

1000

AN:

4824

European-Finnish (FIN)

AF:

0.222

AC:

2347

AN:

10552

Middle Eastern (MID)

AF:

0.120

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.194

AC:

13156

AN:

67960

Other (OTH)

AF:

0.225

AC:

476

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1431

2862

4293

5724

7155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.140

Hom.:

362

Bravo

AF:

0.270

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

3.8

(source)

DANN

Benign

0.31

PhyloP100

-2.5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over