chr15-44572802-T-C

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.6224A>G(p.Asn2075Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,613,944 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2075T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: -0.626

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=0.0044772923).

BP6

Variant 15-44572802-T-C is Benign according to our data. Variant chr15-44572802-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188231.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00264 (401/152130) while in subpopulation AMR AF = 0.00413 (63/15264). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG11	NM_025137.4 link	c.6224A>G	p.Asn2075Ser	missense_variant	Exon 33 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.6224A>G	p.Asn2075Ser	missense_variant	Exon 33 of 40	1	NM_025137.4	ENSP00000261866.7

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00396

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00295

AC:

743

AN:

251490

AF XY:

0.00270

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00371

AC:

5419

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

2548

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33478

American (AMR)

AF:

0.00449

AC:

201

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00440

AC:

115

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000406

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00429

AC:

4765

AN:

1111960

Other (OTH)

AF:

0.00404

AC:

244

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

296

591

887

1182

1478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

194

388

582

776

970

<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:

0.00264

AC:

401

AN:

152130

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41502

American (AMR)

AF:

0.00413

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00396

AC:

269

AN:

67988

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

106

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:

0.00354

Hom.:

Bravo

AF:

0.00288

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00259

AC:

314

EpiCase

AF:

0.00387

EpiControl

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 15, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27066562) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG11: BP4, BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:5

Jul 16, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 19, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 11

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Benign:1

Jun 18, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SPG11-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Jan 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.050

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.031

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.0091

T;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.11

T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0045

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.53

N;.;.;.

PhyloP100

-0.63

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.50

N;N;N;N

REVEL

Benign

0.085

Sift

Benign

0.49

T;T;T;T

Sift4G

Benign

0.65

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.11

MVP

0.28

MPC

0.032

ClinPred

0.0022

GERP RS

-4.8

PromoterAI

-0.0063

Neutral

(source)

Varity_R

0.0098

gMVP

0.054

Mutation Taster

=99/1

polymorphism

(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