rs547634456

Variant names:

• chr15-22823786-C-T
• rs547634456
• NM_144599.5:c.537C>T
• NIPA1 p.Ile179Ile

Your query was ambiguous. Multiple possible variants found:

• chr15-22823786-C-T
• chr15-22823786-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_144599.5(NIPA1):​c.537C>T​(p.Ile179Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,613,516 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 0.00037 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (20 hom.)
• Consequence: NIPA1 NM_144599.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.11
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-22823786-C-T is Benign according to our data. Variant chr15-22823786-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 315424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BS2: High AC in GnomAd4 at 56 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.537C>T	p.Ile179Ile	synonymous	Exon 5 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.312C>T	p.Ile104Ile	synonymous	Exon 5 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.537C>T	p.Ile179Ile	synonymous	Exon 5 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.312C>T	p.Ile104Ile	synonymous	Exon 5 of 5	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.312C>T	p.Ile104Ile	synonymous	Exon 5 of 5	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152208 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00126 AC: 315 AN: 249244 AF XY: 0.00173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000652 AC: 952 AN: 1461190 Hom.: 20 Cov.: 32 AF XY: 0.000912 AC XY: 663 AN XY: 726884

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00896 AC: 773 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53116

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.0000863 AC: 96 AN: 1111754

Other (OTH) AF: 0.000812 AC: 49 AN: 60378

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152326 Hom.: 4 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000172 Hom.: 1

Bravo AF: 0.0000982

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 6 (1)
-	-	1	Spastic paraplegia, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs547634456; hg19: chr15-23049282; COSMIC: COSV61679378; COSMIC: COSV61679378;