NM_025137.4:c.1108G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025137.4(SPG11):c.1108G>A(p.Glu370Lys) variant causes a missense change. The variant allele was found at a frequency of 0.018 in 1,613,924 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.018 ( 311 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.68

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067484677).

BP6

Variant 15-44651839-C-T is Benign according to our data. Variant chr15-44651839-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2483/152252) while in subpopulation NFE AF = 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 33 homozygotes in GnomAd4. There are 1251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.1108G>A	p.Glu370Lys	missense_variant	Exon 6 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.1108G>A	p.Glu370Lys	missense_variant	Exon 6 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2483

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00943

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0171

AC:

4280

AN:

250764

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0445

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0182

AC:

26581

AN:

1461672

Hom.:

311

Cov.:

AF XY:

0.0183

AC XY:

13321

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

33480

American (AMR)

AF:

0.00801

AC:

358

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

625

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00667

AC:

575

AN:

86258

European-Finnish (FIN)

AF:

0.0435

AC:

2320

AN:

53340

Middle Eastern (MID)

AF:

0.0288

AC:

166

AN:

5768

European-Non Finnish (NFE)

AF:

0.0193

AC:

21419

AN:

1111884

Other (OTH)

AF:

0.0168

AC:

1017

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1579

3157

4736

6314

7893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.0163

AC:

2483

AN:

152252

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1251

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41550

American (AMR)

AF:

0.00942

AC:

144

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00643

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0440

AC:

466

AN:

10596

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0229

AC:

1560

AN:

68024

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

125

251

376

502

627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0198

Hom.:

115

Bravo

AF:

0.0125

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.0204

AC:

175

ExAC

AF:

0.0167

AC:

2022

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 11

Benign:5

Jul 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 -

Hereditary spastic paraplegia

Benign:1

Aug 30, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 5

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Benign:1

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

0.0067

T;T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

M;M;.;M;.

PhyloP100

3.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.029

D;D;D;D;D

Sift4G

Benign

0.31

T;T;T;D;D

Polyphen

0.38

B;.;B;.;.

Vest4

0.35

MPC

0.27

ClinPred

0.016

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.35

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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