rs312262786

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_025137.4(SPG11):c.6898_6899delCT(p.Leu2300AlafsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SPG11
NM_025137.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 9.08

Publications

4 publications found

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 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

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 15-44565953-CAG-C is Pathogenic according to our data. Variant chr15-44565953-CAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41354.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.6898_6899delCT	p.Leu2300AlafsTer39	frameshift_variant	Exon 38 of 40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 link	c.6898_6899delCT	p.Leu2300AlafsTer39	frameshift_variant	Exon 38 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251036

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461752

Hom.:

AF XY:

0.00000550

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Pathogenic:2Other:1

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu2300Alafs*39) 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 (rs312262786, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 18835492, 23733235, 27820618, 29691679). This variant is also known as c.6559_6560del (p.L2187fs). ClinVar contains an entry for this variant (Variation ID: 41354). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Nov 03, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPG11-related disorder

Pathogenic:1

Oct 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SPG11 c.6898_6899delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu2300Alafs*39). This variant, also know as c.6559_6560del in an alternate transcript (NM_001160227), has been reported in the compound heterozygous and homozygous states in at least 4 individuals with autosomal recessive spastic paraplegia (Liao et al. 2008. PubMed ID: 18835492; Yoon et al. 2013. PubMed ID: 23733235; Monies et al. 2017. PubMed ID: 28600779; Travaglini et al. 2018. PubMed ID: 29691679) and shown to segregate with disease in one family (Figure 3, Liao et al. 2008. PubMed ID: 18835492). This variant is reported in 0.0004% of alleles (1 of 251,036 total) in gnomAD (http://gnomad.broadinstitute.org/variant/15-44858151-CAG-C). Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over