NM_025137.4:c.1388T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025137.4(SPG11):c.1388T>C(p.Phe463Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,660 control chromosomes in the GnomAD database, including 167,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17741 hom., cov: 32)

Exomes 𝑓: 0.45 ( 150009 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.39

Publications

51 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=4.9492717E-4).

BP6

Variant 15-44651559-A-G is Benign according to our data. Variant chr15-44651559-A-G is described in ClinVar as Benign. ClinVar VariationId is 41271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.1388T>C	p.Phe463Ser	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.1388T>C	p.Phe463Ser	missense_variant	Exon 6 of 40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.481

AC:

73026

AN:

151916

Hom.:

17722

Cov.:

show subpopulations

Gnomad AFR

AF:

0.524

Gnomad AMI

AF:

0.595

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.448

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.468

AC:

117565

AN:

251374

AF XY:

0.458

show subpopulations

Gnomad AFR exome

AF:

0.528

Gnomad AMR exome

AF:

0.568

Gnomad ASJ exome

AF:

0.462

Gnomad EAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.482

Gnomad NFE exome

AF:

0.454

Gnomad OTH exome

AF:

0.469

GnomAD4 exome

AF:

0.451

AC:

659493

AN:

1461626

Hom.:

150009

Cov.:

AF XY:

0.449

AC XY:

326424

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.524

AC:

17536

AN:

33472

American (AMR)

AF:

0.569

AC:

25437

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

12131

AN:

26134

East Asian (EAS)

AF:

0.541

AC:

21486

AN:

39696

South Asian (SAS)

AF:

0.368

AC:

31704

AN:

86252

European-Finnish (FIN)

AF:

0.492

AC:

26287

AN:

53416

Middle Eastern (MID)

AF:

0.360

AC:

2076

AN:

5768

European-Non Finnish (NFE)

AF:

0.446

AC:

495687

AN:

1111784

Other (OTH)

AF:

0.450

AC:

27149

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

20042

40084

60127

80169

100211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15022

30044

45066

60088

75110

<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:

0.481

AC:

73084

AN:

152034

Hom.:

17741

Cov.:

AF XY:

0.480

AC XY:

35695

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.523

AC:

21682

AN:

41442

American (AMR)

AF:

0.543

AC:

8298

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

1613

AN:

3470

East Asian (EAS)

AF:

0.482

AC:

2498

AN:

5184

South Asian (SAS)

AF:

0.367

AC:

1766

AN:

4812

European-Finnish (FIN)

AF:

0.481

AC:

5078

AN:

10554

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.448

AC:

30473

AN:

67984

Other (OTH)

AF:

0.473

AC:

1000

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1982

3964

5946

7928

9910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.459

Hom.:

74625

Bravo

AF:

0.490

TwinsUK

AF:

0.437

AC:

1622

ALSPAC

AF:

0.435

AC:

1678

ESP6500AA

AF:

0.525

AC:

2310

ESP6500EA

AF:

0.456

AC:

3917

ExAC

AF:

0.466

AC:

56539

Asia WGS

AF:

0.462

AC:

1607

AN:

3478

EpiCase

AF:

0.445

EpiControl

AF:

0.454

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Benign:7

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome-Nilou Lab

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 21, 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. -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Amyotrophic lateral sclerosis type 5

Benign:1

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2X

Benign:1

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.039

T;.;T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.81

T;T;T;T;T

MetaRNN

Benign

0.00049

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;M;.;M;.

PhyloP100

1.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.34

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.021

B;.;B;.;.

Vest4

0.20

MPC

0.30

ClinPred

0.016

GERP RS

4.9

Varity_R

0.096

gMVP

0.40

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