NM_025137.4:c.3037A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_025137.4(SPG11):c.3037A>G(p.Lys1013Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,368 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0095 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 129 hom. )

Consequence

SPG11
NM_025137.4 missense, splice_region

Scores

Splicing: ADA: 0.5875

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 1.67

Publications

14 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009679407).

BP6

Variant 15-44615364-T-C is Benign according to our data. Variant chr15-44615364-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194676.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00946 (1441/152346) while in subpopulation AMR AF = 0.0148 (227/15300). AF 95% confidence interval is 0.0133. There are 8 homozygotes in GnomAd4. There are 716 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.3037A>G	p.Lys1013Glu	missense_variant, splice_region_variant	Exon 16 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.3037A>G	p.Lys1013Glu	missense_variant, splice_region_variant	Exon 16 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00946

AC:

1440

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0102

AC:

2564

AN:

251164

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0116

AC:

16941

AN:

1461022

Hom.:

129

Cov.:

AF XY:

0.0118

AC XY:

8553

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33466

American (AMR)

AF:

0.0115

AC:

513

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

411

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00818

AC:

705

AN:

86220

European-Finnish (FIN)

AF:

0.00139

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.0126

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.0130

AC:

14455

AN:

1111812

Other (OTH)

AF:

0.0107

AC:

645

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

837

1674

2511

3348

4185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.00946

AC:

1441

AN:

152346

Hom.:

Cov.:

AF XY:

0.00961

AC XY:

716

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41588

American (AMR)

AF:

0.0148

AC:

227

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0134

AC:

914

AN:

68028

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

145

217

290

362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0128

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.00992

AC:

1205

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0178

EpiControl

AF:

0.0169

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Benign:6

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), but has also been identified in >1% of European (non-Finnish) chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for spastic paraplegia. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Mar 16, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 04, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Amyotrophic lateral sclerosis

Uncertain:1

Sep 09, 2020

UM ALS/MND Lab, University Of Malta

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Hereditary spastic paraplegia

Benign:1

Oct 12, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG11: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

T;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.082

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.72

T;T;T;T

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.2

L;L;.;L

PhyloP100

1.7

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.46

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.44

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0020

B;.;B;.

Vest4

0.25

MPC

0.047

ClinPred

0.0030

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.27

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.10

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