16-89546715-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_003119.4(SPG7):c.1507A>G(p.Thr503Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,612,768 control chromosomes in the GnomAD database, including 26,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T503I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1673 hom., cov: 31)

Exomes 𝑓: 0.18 ( 24659 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.86

Publications

64 publications found

Variant links:

Genes affected

SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

SPG7 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 7
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPG7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003119.4

BP4

Computational evidence support a benign effect (MetaRNN=0.001221776).

BP6

Variant 16-89546715-A-G is Benign according to our data. Variant chr16-89546715-A-G is described in ClinVar as Benign. ClinVar VariationId is 130369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.1507A>G	p.Thr503Ala	missense_variant	Exon 11 of 17	ENST00000645818.2	NP_003110.1	Q9UQ90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.1507A>G	p.Thr503Ala	missense_variant	Exon 11 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.131

AC:

19881

AN:

151904

Hom.:

1675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0357

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.0853

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.162

GnomAD2 exomes

AF:

0.149

AC:

37389

AN:

251458

AF XY:

0.153

show subpopulations

Gnomad AFR exome

AF:

0.0319

Gnomad AMR exome

AF:

0.0888

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.0899

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.170

GnomAD4 exome

AF:

0.179

AC:

261436

AN:

1460746

Hom.:

24659

Cov.:

AF XY:

0.179

AC XY:

129777

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.0286

AC:

958

AN:

33472

American (AMR)

AF:

0.0930

AC:

4159

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

5773

AN:

26132

East Asian (EAS)

AF:

0.130

AC:

5159

AN:

39694

South Asian (SAS)

AF:

0.144

AC:

12377

AN:

86246

European-Finnish (FIN)

AF:

0.0962

AC:

5139

AN:

53396

Middle Eastern (MID)

AF:

0.178

AC:

1025

AN:

5768

European-Non Finnish (NFE)

AF:

0.195

AC:

216153

AN:

1110962

Other (OTH)

AF:

0.177

AC:

10693

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

10715

21431

32146

42862

53577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7476

14952

22428

29904

37380

<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:

0.131

AC:

19872

AN:

152022

Hom.:

1673

Cov.:

AF XY:

0.126

AC XY:

9371

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0356

AC:

1478

AN:

41508

American (AMR)

AF:

0.121

AC:

1843

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

828

AN:

3470

East Asian (EAS)

AF:

0.144

AC:

738

AN:

5132

South Asian (SAS)

AF:

0.147

AC:

706

AN:

4808

European-Finnish (FIN)

AF:

0.0853

AC:

902

AN:

10574

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.187

AC:

12700

AN:

67950

Other (OTH)

AF:

0.163

AC:

343

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

884

1768

2653

3537

4421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.174

Hom.:

12195

Bravo

AF:

0.129

TwinsUK

AF:

0.197

AC:

732

ALSPAC

AF:

0.205

AC:

789

ESP6500AA

AF:

0.0382

AC:

168

ESP6500EA

AF:

0.194

AC:

1666

ExAC

AF:

0.151

AC:

18294

Asia WGS

AF:

0.110

AC:

381

AN:

3478

EpiCase

AF:

0.197

EpiControl

AF:

0.198

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Jul 31, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Allele frequency 14% of total chromosomes by gnomad (http://gnomad.broadinstitut e.org). -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D;D;D;T;T;D;D;D

MetaRNN

Benign

0.0012

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.36

.;.;N;.;.;.;.;.;.

PhyloP100

1.9

PrimateAI

Benign

0.29

REVEL

Benign

0.29

Polyphen

0.0

.;.;B;.;.;.;.;.;.

MPC

0.20

ClinPred

0.0073

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.25

Mutation Taster

=90/10

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