15-22812251-C-G

Variant names:

• chr15-22812251-C-G
• rs373273269
• NM_144599.5:c.315C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_144599.5(NIPA1):​c.315C>G​(p.Phe105Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F105F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NIPA1 NM_144599.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.736
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_144599.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.315C>G	p.Phe105Leu	missense splice_region	Exon 3 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.90C>G	p.Phe30Leu	missense splice_region	Exon 3 of 5	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.315C>G	p.Phe105Leu	missense splice_region	Exon 3 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.90C>G	p.Phe30Leu	missense splice_region	Exon 3 of 5	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.90C>G	p.Phe30Leu	missense splice_region	Exon 3 of 5	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451908 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722908

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103058

Other (OTH) AF: 0.00 AC: 0 AN: 60038

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
LIST_S2	Uncertain	0.88	D
MetaRNN	Uncertain	0.70	D
PhyloP100		0.74
PROVEAN	Benign	0.26	N
Sift	Uncertain	0.019	D
Sift4G	Benign	0.30	T
Vest4		0.88
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

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

Other links and lift over

dbSNP: rs373273269; hg19: chr15-23060817;