15-22786673-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. A6V) 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:2 B: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: Benign. The variant received -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 VariationId is 447766.
• BS2: High AC in GnomAd4 at 7 AD gene.

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>G	p.Ala6Gly	missense	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+425C>G		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>G	p.Ala6Gly	missense	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12360C>G		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+425C>G		intron	N/A	ENSP00000453722.1	Q7RTP0-2

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

African (AFR) AF: 0.0000564 AC: 1 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: 0.00 AC: 0 AN: 9038

South Asian (SAS) AF: 0.00 AC: 0 AN: 22724

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: 0.0000964 AC: 80 AN: 830146

Other (OTH) AF: 0.000151 AC: 5 AN: 33110

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

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: 0.000110 AC: 7 AN: 63432

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 6 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.8
PROVEAN	Benign	0.31	N
Sift	Benign	0.39	T
Sift4G	Benign	0.15	T
Vest4		0.34
PromoterAI		-0.15	Neutral
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

Other links and lift over

dbSNP: rs944860201; hg19: chr15-23086395;