Variant rs312262722 details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000261866.12(SPG11):c.1203del(p.Asp402IlefsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,084 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SPG11
ENST00000261866.12 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 0.0150

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 15-44651743-CT-C is Pathogenic according to our data. Variant chr15-44651743-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 41268.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 linkuse as main transcript	c.1203del	p.Asp402IlefsTer14	frameshift_variant	6/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.1203del	p.Asp402IlefsTer14	frameshift_variant	6/40	1	NM_025137.4	ENSP00000261866		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251420

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2023	This sequence change creates a premature translational stop signal (p.Asp402Ilefs*14) 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 (rs312262722, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41268). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 17322883, 19105190, 19196735, 24833714). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2022

The c.1203delA pathogenic mutation, located in coding exon 6 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 1203, causing a translational frameshift with a predicted alternate stop codon (p.D402Ifs*14). This alteration has been detected as homozygous or compound heterozygous with another SPG11 alteration in multiple individuals with hereditary spastic paraplegia type 11 (SPG11) (Vural A et al. Mov Disord, 2021 07;36:1676-1688). (Chen X et al. BMC Neurol, 2020 Jan;20:2; D'Amore A et al. Front Neurol, 2018 Dec;9:981; Pensato V et al. Brain, 2014 Jul;137:1907-20; de Bot ST et al. Eur J Hum Genet, 2013 Nov;21:1312-5; Crimella C et al. J Med Genet, 2009 May;46:345-51; Denora PS et al. Hum Mutat, 2009 Mar;30:E500-19; Stevanin G et al. Nat Genet, 2007 Mar;39:366-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

SPG11-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The SPG11 c.1203delA variant is predicted to result in a frameshift and premature protein termination (p.Asp402Ilefs*14). This variant was reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive spastic paraplegia (Stevanin et al. 2007. PubMed ID: 17322883; D'Amore et al. 2018. PubMed ID: 30564185; Table S1, Vural et al. 2021. PubMed ID: 33624863). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 18, 2024

ACMG categories: PVS1,PS4,PM2,PM3 -

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

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