rs147356553

Variant names:

• chr15-22786362-G-C
• rs147356553
• ENST00000437912.6:c.-48+12049G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001142275.1(NIPA1):​c.-48+114G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00881 in 153,700 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: NIPA1 NM_001142275.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.310
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-22786362-G-C is Benign according to our data. Variant chr15-22786362-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1194677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00888 (1353/152312) while in subpopulation AFR AF = 0.0307 (1278/41572). AF 95% confidence interval is 0.0293. There are 24 homozygotes in GnomAd4. There are 641 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1353 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142275.1. 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_001142275.1		c.-48+114G>C		intron	N/A	NP_001135747.1	Q8TAY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12049G>C		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+114G>C		intron	N/A	ENSP00000453722.1	Q7RTP0-2
	NIPA1	ENST00000560069.5	TSL:4	n.31+114G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1350 AN: 152194 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

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: 0.0000735

Gnomad OTH AF: 0.00957

GnomAD4 exome AF: 0.000720 AC: 1 AN: 1388 Hom.: 0 AF XY: 0.00119 AC XY: 1 AN XY: 840

African (AFR) AF: 0.0385 AC: 1 AN: 26

American (AMR) AF: 0.00 AC: 0 AN: 66

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 28

East Asian (EAS) AF: 0.00 AC: 0 AN: 38

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 92

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1034

Other (OTH) AF: 0.00 AC: 0 AN: 92

GnomAD4 genome AF: 0.00888 AC: 1353 AN: 152312 Hom.: 24 Cov.: 32 AF XY: 0.00861 AC XY: 641 AN XY: 74482

African (AFR) AF: 0.0307 AC: 1278 AN: 41572

American (AMR) AF: 0.00327 AC: 50 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00763 Hom.: 2

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-0.31
PromoterAI		-0.00010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs147356553; hg19: chr15-23086706;