rs749414711

Variant names:

• chr15-22786677-A-G
• rs749414711
• NM_144599.5:c.21A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-22786677-A-G
• chr15-22786677-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_144599.5(NIPA1):​c.21A>G​(p.Ala7Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,071,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NIPA1 NM_144599.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.16
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-22786677-A-G is Benign according to our data. Variant chr15-22786677-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380931.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 39 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.21A>G	p.Ala7Ala	synonymous	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+429A>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.21A>G	p.Ala7Ala	synonymous	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12364A>G		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+429A>G		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 39 AN: 145408 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000259

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000639 AC: 7 AN: 10952 AF XY: 0.000931

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000333 AC: 308 AN: 926086 Hom.: 0 Cov.: 20 AF XY: 0.000296 AC XY: 131 AN XY: 442822

African (AFR) AF: 0.000172 AC: 3 AN: 17460

American (AMR) AF: 0.000171 AC: 1 AN: 5856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8166

East Asian (EAS) AF: 0.000449 AC: 4 AN: 8916

South Asian (SAS) AF: 0.000596 AC: 13 AN: 21810

European-Finnish (FIN) AF: 0.000125 AC: 1 AN: 8024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2628

European-Non Finnish (NFE) AF: 0.000341 AC: 280 AN: 820594

Other (OTH) AF: 0.000184 AC: 6 AN: 32632

GnomAD4 genome AF: 0.000268 AC: 39 AN: 145490 Hom.: 0 Cov.: 27 AF XY: 0.000268 AC XY: 19 AN XY: 70786

African (AFR) AF: 0.000348 AC: 14 AN: 40200

American (AMR) AF: 0.0000676 AC: 1 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4816

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4698

European-Finnish (FIN) AF: 0.000566 AC: 5 AN: 8836

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.000259 AC: 17 AN: 65560

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.000506 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia 6 (2)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		-1.2
PromoterAI		-0.050	Neutral

Splicing

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

Other links and lift over

dbSNP: rs749414711; hg19: chr15-23086391; COSMIC: COSV61679685; COSMIC: COSV61679685;