Genetic Variant NIPA1:p.Thr45Met (chr15-22786790-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_144599.5(NIPA1):c.134C>T(p.Thr45Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000865 in 1,155,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T45R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

NIPA1
NM_144599.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

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

NIPA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-22786790-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5 link	c.134C>T	p.Thr45Met	missense_variant	Exon 1 of 5	ENST00000337435.9	NP_653200.2	Q7RTP0-1
NIPA1	NM_001142275.1 link	c.-48+542C>T		intron_variant	Intron 1 of 4		NP_001135747.1	Q7RTP0-2A0A024R344Q8TAY1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9 link	c.134C>T	p.Thr45Met	missense_variant	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4		Q7RTP0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.65e-7

AC:

AN:

1155566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

573050

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23600

American (AMR)

AF:

0.00

AC:

AN:

29144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16138

East Asian (EAS)

AF:

0.00

AC:

AN:

16038

South Asian (SAS)

AF:

0.0000158

AC:

AN:

63092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4380

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

937220

Other (OTH)

AF:

0.00

AC:

AN:

42122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

LIST_S2

Uncertain

0.87

MetaRNN

Uncertain

0.56

PhyloP100

1.1

PROVEAN

Uncertain

-2.4

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.48

PromoterAI

0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over