15-22786790-C-T

Variant names:

• chr15-22786790-C-T
• rs104894496
• NM_144599.5:c.134C>T
• NIPA1 p.Thr45Met

GermlineCancer (beta)

Variant summary

Our verdict is

Uncertain significance

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 3 classification points (ACMG Germline Pathogenicity v2019): 3P and 0B. PM2_SupportingPM5

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 has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000158, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (AlphaMissense) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T45R: Pathogenic (ClinVar VariationId 2520, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T45K: Uncertain_significance (ClinVar VariationId 2684018, 1 star)

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 3 points.

• PM2: Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000158 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.T45R: Pathogenic (ClinVar VariationId 2520, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.T45K: Uncertain_significance (ClinVar VariationId 2684018, 1 star)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	NM_144599.5	MANE Select	c.134C>T	p.Thr45Met	missense	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+542C>T		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.134C>T	p.Thr45Met	missense	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12477C>T		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+542C>T		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.65e-7 AC: 1 AN: 1155566 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 573050

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

African (AFR) AF: 0.00 AC: 0 AN: 23600

American (AMR) AF: 0.00 AC: 0 AN: 29144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16138

East Asian (EAS) AF: 0.00 AC: 0 AN: 16038

South Asian (SAS) AF: 0.0000158 AC: 1 AN: 63092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4380

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937220

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Uncertain	0.56	D
PhyloP100		1.1
PROVEAN	Uncertain	-2.4	N
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
PromoterAI		0.19	Neutral
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894496;

hg19: chr15-23086278;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar