rs312262709

chr15-44660607-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025137.4(SPG11):c.267G>A(p.Trp89Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPG11 NM_025137.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 4.81

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 18 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 15-44660607-C-T is Pathogenic according to our data. Variant chr15-44660607-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 41294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.267G>A	p.Trp89Ter	stop_gained	2/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.267G>A	p.Trp89Ter	stop_gained	2/40	1	NM_025137.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251148 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727206

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (Orlacchio A et.al.,2010). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003982% is reported in gnomAD. Loss-of-function variants in SPG11 are known to be pathogenic. The nucleotide change in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 23, 2022	A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases . The in silico prediction# of the variant is damaging by MutationTaster2. The reference codon is conserved across species. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change creates a premature translational stop signal (p.Trp89*) 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 present in population databases (rs312262709, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (PMID: 18067136, 20110243, 27217339). ClinVar contains an entry for this variant (Variation ID: 41294). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPG11: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717728, 26971897, 30574063, 20110243, 18067136) -

Amyotrophic lateral sclerosis type 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Mar 02, 2024

A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 (p.Trp89Ter) was detected. The observed variant has previously been reported in patients affected with hereditary spastic paraplegia [PMID: 27217339]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.67
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs312262709; hg19: chr15-44952805;