rs864622190

Variant names:

• chr15-44563202-TTC-AACAG
• rs864622190
• NM_025137.4:c.7249_7251delGAAinsCTGTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_025137.4(SPG11):​c.7249_7251delGAAinsCTGTT​(p.Glu2417LeufsTer9) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2417K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 NM_025137.4 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.70
• Publications: 0 publications found

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

EIF3J (HGNC:3270): (eukaryotic translation initiation factor 3 subunit J) This gene encodes a core subunit of the eukaryotic initiation factor 3 complex, which participates in the initiation of translation by aiding in the recruitment of protein and mRNA components to the 40S ribosome. There are pseudogenes for this gene on chromosomes 1, 3, and 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0113 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025137.4. 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
	SPG11	NM_025137.4	MANE Select	c.7249_7251delGAAinsCTGTT	p.Glu2417LeufsTer9	frameshift missense	Exon 40 of 40	NP_079413.3
	SPG11	NM_001411132.1		c.7105_7107delGAAinsCTGTT	p.Glu2369LeufsTer9	frameshift missense	Exon 40 of 40	NP_001398061.1
	SPG11	NM_001160227.2		c.6910_6912delGAAinsCTGTT	p.Glu2304LeufsTer9	frameshift missense	Exon 38 of 38	NP_001153699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG11	ENST00000261866.12	TSL:1 MANE Select	c.7249_7251delGAAinsCTGTT	p.Glu2417LeufsTer9	frameshift missense	Exon 40 of 40	ENSP00000261866.7
	SPG11	ENST00000535302.6	TSL:1	c.6910_6912delGAAinsCTGTT	p.Glu2304LeufsTer9	frameshift missense	Exon 38 of 38	ENSP00000445278.2
	SPG11	ENST00000427534.6	TSL:1	c.*54_*56delGAAinsCTGTT		3_prime_UTR	Exon 37 of 37	ENSP00000396110.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

Other links and lift over

dbSNP: rs864622190; hg19: chr15-44855400;