rs312262730

Positions:

• chr15-44648915-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_025137.4(SPG11):​c.1551_1552del​(p.Cys518SerfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPG11 NM_025137.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-44648915-CAA-C is Pathogenic according to our data. Variant chr15-44648915-CAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41275.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.1551_1552del	p.Cys518SerfsTer39	frameshift_variant	7/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.1551_1552del	p.Cys518SerfsTer39	frameshift_variant	7/40	1	NM_025137.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461832 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:1 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Cys518Serfs*39) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18663179). This variant is also known as c.1550_1551delTT (p.L517fsX556). ClinVar contains an entry for this variant (Variation ID: 41275). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 30, 2018	The SPG11 c.1551_1552delTT (p.Cys518SerfsTer39) variant is a frameshift variant and is predicted to result in a premature truncation of the protein. The p.Cys518SerfsTer39 variant, also reported as p.Leu517ValfsTer16 in literature, has been reported in two studies, in which it is found in a total of three individuals with spastic paraplegia, including in two siblings in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Samaranch et al. 2008; Zhang et al. 2016). In one family, two affected siblings presented with autosomal recessive hereditary spastic paraplegia with thin corpus callosum. The variant was absent from 100 Chinese control subjects. The p.Cys518SerfsTer39 variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage, and so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and limited evidence, the p.Cys518SerfsTer39 variants classified as a variant of unknown significance but suspicious for autosomal recessive spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs312262730; hg19: chr15-44941113;