NM_144599.5:c.17C>T

Variant names:

• chr15-22786673-C-T
• rs944860201
• NM_144599.5:c.17C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_144599.5(NIPA1):​c.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000651 in 1,075,406 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16161433).

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.17C>T	p.Ala6Val	missense	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+425C>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.17C>T	p.Ala6Val	missense	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12360C>T		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+425C>T		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.00000734 AC: 1 AN: 136294 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000158

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 11734 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 6 AN: 939112 Hom.: 0 Cov.: 21 AF XY: 0.00000890 AC XY: 4 AN XY: 449308

⚠️ 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: 17736

American (AMR) AF: 0.00 AC: 0 AN: 6768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8390

East Asian (EAS) AF: 0.000111 AC: 1 AN: 9038

South Asian (SAS) AF: 0.0000440 AC: 1 AN: 22722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2710

European-Non Finnish (NFE) AF: 0.00000482 AC: 4 AN: 830138

Other (OTH) AF: 0.00 AC: 0 AN: 33110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0182698), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000734 AC: 1 AN: 136294 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 1 AN XY: 66042

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

African (AFR) AF: 0.00 AC: 0 AN: 36272

American (AMR) AF: 0.00 AC: 0 AN: 13332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000158 AC: 1 AN: 63432

Other (OTH) AF: 0.00 AC: 0 AN: 1912

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.16	T
PhyloP100		2.8
PROVEAN	Benign	-0.22	N
Sift	Uncertain	0.015	D
Sift4G	Benign	0.18	T
Vest4		0.40
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs944860201; hg19: chr15-23086395;