rs312262734

Variant names:

• chr15-44633498-CACTT-C
• rs312262734
• NM_025137.4:c.1735+3_1735+6delAAGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate 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
• Publications: 2 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]

SPG11 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina, G2P
• amyotrophic lateral sclerosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2X

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-44633498-CACTT-C is Pathogenic according to our data. Variant chr15-44633498-CACTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 41281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4	c.1735+3_1735+6delAAGT		splice_region_variant, intron_variant	Intron 8 of 39	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.1735+3_1735+6delAAGT		splice_region_variant, intron_variant	Intron 8 of 39	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

African (AFR) AF: 0.00 AC: 0 AN: 32620

American (AMR) AF: 0.00 AC: 0 AN: 43338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 83328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085904

Other (OTH) AF: 0.00 AC: 0 AN: 59368

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Jan 31, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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 also known as c.1735+2_+7delAAGT. ClinVar contains an entry for this variant (Variation ID: 41281). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SPG11 function (PMID: 19196735). 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. For these reasons, this variant has been classified as Pathogenic. -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1

Jun 14, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PS3, PP4, PP3, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs312262734; hg19: chr15-44925696;