Variant rs312262784 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025137.4(SPG11):c.6832_6833del(p.Ser2278LeufsTer61) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.46

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 15-44566226-ACT-A is Pathogenic according to our data. Variant chr15-44566226-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 41351.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 linkuse as main transcript	c.6832_6833del	p.Ser2278LeufsTer61	frameshift_variant	37/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.6832_6833del	p.Ser2278LeufsTer61	frameshift_variant	37/40	1	NM_025137.4		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251356

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461880

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The homozygous p.Ser2278LeufsTer61 variant in SPG11 was identified by our study in one individual with spastic paraplegia. The p.Ser2278LeufsTer61 variant in SPG11 has been previously reported in 4 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 27084228, PMID: 26556829, PMID: 22237444, PMID: 18079167) and segregated with disease in 4 affected relatives from 2 families (PMID: 26556829, PMID: 18079167), but has been identified in 0.005% (1/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262784). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 affected unrelated individuals PMID: 27084228, PMID: 26556829, PMID: 22237444, PMID: 18079167), two were homozygotes (PMID: 18079167, PMID: 26556829), one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 27084228) and one was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 22237444). This variant has also been reported in ClinVar (Variation ID: 41351) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 2278 and leads to a premature termination codon 61 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive spastic paraplegia 11. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia 11. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Ser2278Leufs*61) 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 (rs312262784, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with SPG11-related conditions (PMID: 18079167, 21035867, 22237444, 26556829, 27084228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41351). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 22, 2021	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.6832_6833delAG pathogenic mutation, located in coding exon 37 of the SPG11 gene, results from a deletion of two nucleotides at nucleotide positions 6832 to 6833, causing a translational frameshift with a predicted alternate stop codon (p.S2278Lfs*61). This variant has been reported in the homozygous and compound heterozygous states in multiple patients with hereditary spastic paraplegia and/or Charcot-Marie-Tooth disease (Stevanin G et al. Brain, 2008 Mar;131:772-84; Conceição Pereira M et al. Genet Med, 2012 Jan;14:143-51; Balicza P et al. J Neurol Sci, 2016 May;364:116-21; Montecchiani C et al. Brain, 2016 Jan;139:73-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2018

The p.Ser2278LeufsX61 variant in SPG11 has been reported in the homozygous or compound heterozygous state in at least 3 individuals with hereditary spastic paraplegia (HSP) and 1 individual with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2; Stevanin 2008, Conceicao Pereira 2012, Montecchiani 2016, Balicza 2016). It segregated with disease in two affected members of two families; one with HSP and one with CMT2. This variant has also been identified in 0.01% (1/17244) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2278 and leads to a premature termination codon 61 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for spastic paraplegia in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over