NM_144599.5:c.441A>G

Variant names:

• chr15-22820436-A-G
• rs11263683
• NM_144599.5:c.441A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144599.5(NIPA1):​c.441A>G​(p.Thr147Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 1,611,202 control chromosomes in the GnomAD database, including 431,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35508 hom., cov: 32)
  • Exomes 𝑓: 0.73 (396328 hom.)
• Consequence: NIPA1 NM_144599.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.55
• Publications: 25 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-22820436-A-G is Benign according to our data. Variant chr15-22820436-A-G is described in ClinVar as Benign. ClinVar VariationId is 129804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

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.441A>G	p.Thr147Thr	synonymous	Exon 4 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.216A>G	p.Thr72Thr	synonymous	Exon 4 of 5	NP_001135747.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPA1	ENST00000337435.9	TSL:1 MANE Select	c.441A>G	p.Thr147Thr	synonymous	Exon 4 of 5	ENSP00000337452.4
	NIPA1	ENST00000437912.6	TSL:1	c.216A>G	p.Thr72Thr	synonymous	Exon 4 of 5	ENSP00000393962.2
	NIPA1	ENST00000561183.5	TSL:1	c.216A>G	p.Thr72Thr	synonymous	Exon 4 of 5	ENSP00000453722.1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101976 AN: 151912 Hom.: 35486 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.697

GnomAD2 exomes AF: 0.745 AC: 187314 AN: 251454 AF XY: 0.749

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.866

Gnomad ASJ exome AF: 0.794

Gnomad EAS exome AF: 0.819

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.734 AC: 1071301 AN: 1459172 Hom.: 396328 Cov.: 39 AF XY: 0.738 AC XY: 535601 AN XY: 726056

African (AFR) AF: 0.479 AC: 16029 AN: 33442

American (AMR) AF: 0.859 AC: 38411 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 20706 AN: 26126

East Asian (EAS) AF: 0.789 AC: 31301 AN: 39696

South Asian (SAS) AF: 0.847 AC: 73047 AN: 86212

European-Finnish (FIN) AF: 0.637 AC: 34027 AN: 53400

Middle Eastern (MID) AF: 0.726 AC: 4185 AN: 5764

European-Non Finnish (NFE) AF: 0.729 AC: 809190 AN: 1109516

Other (OTH) AF: 0.736 AC: 44405 AN: 60292

GnomAD4 genome AF: 0.671 AC: 102037 AN: 152030 Hom.: 35508 Cov.: 32 AF XY: 0.672 AC XY: 49963 AN XY: 74318

African (AFR) AF: 0.489 AC: 20261 AN: 41440

American (AMR) AF: 0.793 AC: 12122 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2712 AN: 3472

East Asian (EAS) AF: 0.807 AC: 4159 AN: 5154

South Asian (SAS) AF: 0.860 AC: 4149 AN: 4826

European-Finnish (FIN) AF: 0.643 AC: 6789 AN: 10566

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49424 AN: 67966

Other (OTH) AF: 0.699 AC: 1478 AN: 2114

Alfa AF: 0.715 Hom.: 150169

Bravo AF: 0.675

Asia WGS AF: 0.811 AC: 2823 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Hereditary spastic paraplegia 6 (4)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.73
DANN	Benign	0.42
PhyloP100		-5.6

Splicing

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

Other links and lift over

dbSNP: rs11263683; hg19: chr15-23052632; COSMIC: COSV61680320;