15-44622346-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_025137.4(SPG11):c.2318T>G(p.Val773Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000172 in 1,547,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V773I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SPG11
NM_025137.4 missense, splice_region

Scores

Splicing: ADA: 0.6380

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 6.47

Publications

6 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.2318T>G	p.Val773Gly	missense_variant, splice_region_variant	Exon 13 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.2318T>G	p.Val773Gly	missense_variant, splice_region_variant	Exon 13 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

229816

AF XY:

0.000112

show subpopulations

Gnomad AFR exome

AF:

0.000138

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:

0.000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000175

AC:

244

AN:

1395638

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

124

AN XY:

696032

show subpopulations

African (AFR)

AF:

0.0000644

AC:

AN:

31072

American (AMR)

AF:

0.00

AC:

AN:

40818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

39076

South Asian (SAS)

AF:

0.00

AC:

AN:

80402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4818

European-Non Finnish (NFE)

AF:

0.000221

AC:

235

AN:

1063942

Other (OTH)

AF:

0.000121

AC:

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

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

AF:

0.000144

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41560

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.0000661

AC:

EpiCase

AF:

0.000166

EpiControl

AF:

0.000361

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Feb 13, 2020

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 20, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in the heterozygous state as a variant of uncertain significance in an individual with ALS; segregation not performed (Shepheard et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33589474) -

Hereditary spastic paraplegia 11

Uncertain:3

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant, NM_025137.3(SPG11):c.2318T>G, has been identified in exon 12 of 40 of the SPG11 gene. The variant is predicted to result in a major amino acid change from valine to glycine at position 773 of the protein (NP_079413.3(SPG11):p.(Val773Gly)). The valine residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.01% (34 heterozygotes, 0 homozygotes). The variant has been previously described as a variant of certain significant (ClinVar, MSeqDR database). A different variant in the same codon resulting in a change to leucine has also been reported as a vaiant of uncertain significance (ClinVar, MSeqDR database). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 773 of the SPG11 protein (p.Val773Gly). This variant is present in population databases (rs182080501, gnomAD 0.02%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 33589474). ClinVar contains an entry for this variant (Variation ID: 212292). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 09, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2318T>G (p.V773G) alteration is located in exon 13 (coding exon 13) of the SPG11 gene. This alteration results from a T to G substitution at nucleotide position 2318, causing the valine (V) at amino acid position 773 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Jun 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 5

Uncertain:1

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Uncertain:1

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.8

M;M;.;M

PhyloP100

6.5

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.56

MVP

0.89

MPC

0.29

ClinPred

0.90

GERP RS

5.5

Varity_R

0.75

gMVP

0.69

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.64

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.13

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over