15-22786673-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_144599.5(NIPA1):c.17C>G(p.Ala6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000865 in 1,075,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: NIPA1 NM_144599.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.80

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113498926).
• BP6: Variant 15-22786673-C-G is Benign according to our data. Variant chr15-22786673-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447766.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPA1	NM_144599.5	c.17C>G	p.Ala6Gly	missense_variant	1/5	ENST00000337435.9
NIPA1	NM_001142275.1	c.-48+425C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPA1	ENST00000337435.9	c.17C>G	p.Ala6Gly	missense_variant	1/5	1	NM_144599.5	P1
NIPA1	ENST00000437912.6	c.-48+12360C>G		intron_variant		1
NIPA1	ENST00000561183.5	c.-48+425C>G		intron_variant		1
NIPA1	ENST00000560069.5	n.31+425C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000514 AC: 7 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: 0.000110

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000916 AC: 86 AN: 939122 Hom.: 0 Cov.: 21 AF XY: 0.0000979 AC XY: 44 AN XY: 449314

Gnomad4 AFR exome AF: 0.0000564

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000964

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.0000514 AC: 7 AN: 136294 Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 3 AN XY: 66042

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000110

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 17, 2016

- -

Hereditary spastic paraplegia 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.047	T
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.11	T
PROVEAN	Benign	0.31	N
Sift	Benign	0.39	T
Sift4G	Benign	0.15	T
Vest4		0.34
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs944860201; hg19: chr15-23086395;