chr15-22786701-G-A

Variant names:

• chr15-22786701-G-A
• rs1555371616
• NM_144599.5:c.45G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_144599.5(NIPA1):​c.45G>A​(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000204 in 978,686 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: NIPA1 NM_144599.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 15-22786701-G-A is Benign according to our data. Variant chr15-22786701-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 533367.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPA1	NM_144599.5	c.45G>A	p.Ala15Ala	synonymous_variant	Exon 1 of 5	ENST00000337435.9	NP_653200.2
NIPA1	NM_001142275.1	c.-48+453G>A		intron_variant	Intron 1 of 4		NP_001135747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPA1	ENST00000337435.9	c.45G>A	p.Ala15Ala	synonymous_variant	Exon 1 of 5	1	NM_144599.5	ENSP00000337452.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000204 AC: 2 AN: 978686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 472720

African (AFR) AF: 0.00 AC: 0 AN: 18244

American (AMR) AF: 0.00 AC: 0 AN: 7118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11056

East Asian (EAS) AF: 0.00 AC: 0 AN: 10834

South Asian (SAS) AF: 0.00 AC: 0 AN: 29428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2964

European-Non Finnish (NFE) AF: 0.00000235 AC: 2 AN: 852228

Other (OTH) AF: 0.00 AC: 0 AN: 34940

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 6 Benign:1

Dec 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		0.0
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.3

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: rs1555371616; hg19: chr15-23086367;