15-44633498-CACTT-C

Position:

• chr15-44633498-CACTT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_025137.4(SPG11):​c.1735+3_1735+6delAAGT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000014 in 1,428,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPG11 NM_025137.4 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.48

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]

SPG11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-44633498-CACTT-C is Pathogenic according to our data. Variant chr15-44633498-CACTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.1735+3_1735+6delAAGT		splice_region_variant, intron_variant		ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.1735+3_1735+6delAAGT		splice_region_variant, intron_variant		1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428688 Hom.: 0 AF XY: 0.00000281 AC XY: 2 AN XY: 712244

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed splice region c.1735+3_1735+6del variant in SPG11 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Hereditary spastic paraplegia (HSP) (Crimella et al., 2009). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. This splice region variant in intron 8 affects the position three to six nucleotides downstream of exon 7. The spliceAI tool predicts that this splice site variant is damaging. Experimental studies have shown that this variant affects SPG11 function (Crimella et al., 2009). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Jan 31, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	This variant is also known as c.1735+2_+7delAAGT. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects SPG11 function (PMID: 19196735). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 41281). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 19196735; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the SPG11 gene. It does not directly change the encoded amino acid sequence of the SPG11 protein. It affects a nucleotide within the consensus splice site. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Jun 14, 2023

PM3, PS3, PP4, PP3, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs312262734; hg19: chr15-44925696;