chr15-22786671-T-TGCG

Variant names:

• chr15-22786671-T-TGCG
• rs1555371601
• NM_144599.5:c.18_20dupGGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_144599.5(NIPA1):​c.18_20dupGGC​(p.Ala7dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 926,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: NIPA1 NM_144599.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_144599.5
• BP6: Variant 15-22786671-T-TGCG is Benign according to our data. Variant chr15-22786671-T-TGCG is described in ClinVar as Likely_benign. ClinVar VariationId is 3668459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 45 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.18_20dupGGC	p.Ala7dup	disruptive_inframe_insertion	Exon 1 of 5	NP_653200.2
	NIPA1	NM_001142275.1		c.-48+426_-48+428dupGGC		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.18_20dupGGC	p.Ala7dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000337452.4	Q7RTP0-1
	NIPA1	ENST00000437912.6	TSL:1	c.-48+12361_-48+12363dupGGC		intron	N/A	ENSP00000393962.2	Q7RTP0-2
	NIPA1	ENST00000561183.5	TSL:1	c.-48+426_-48+428dupGGC		intron	N/A	ENSP00000453722.1	Q7RTP0-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.000183 AC: 2 AN: 10952 AF XY: 0.000310

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: 0.000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000485 AC: 45 AN: 926956 Hom.: 0 Cov.: 21 AF XY: 0.0000428 AC XY: 19 AN XY: 443684

African (AFR) AF: 0.00 AC: 0 AN: 17566

American (AMR) AF: 0.00 AC: 0 AN: 6766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8322

East Asian (EAS) AF: 0.00 AC: 0 AN: 8778

South Asian (SAS) AF: 0.00 AC: 0 AN: 22658

European-Finnish (FIN) AF: 0.000122 AC: 1 AN: 8230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2652

European-Non Finnish (NFE) AF: 0.0000525 AC: 43 AN: 819304

Other (OTH) AF: 0.0000306 AC: 1 AN: 32680

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.034

Splicing

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

Other links and lift over

dbSNP: rs1555371601; hg19: chr15-23086397;