NM_003119.4:c.2063G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_003119.4(SPG7):c.2063G>A(p.Arg688Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,612,442 control chromosomes in the GnomAD database, including 26,151 homozygotes. In-silico tool predicts 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. R688W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.13 ( 1644 hom., cov: 33)

Exomes 𝑓: 0.18 ( 24507 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.61

Publications

66 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 -16 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, 8 uncertain in NM_003119.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89553919-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1380458.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.0019080639).

BP6

Variant 16-89553920-G-A is Benign according to our data. Variant chr16-89553920-G-A is described in ClinVar as [Benign]. Clinvar id is 130370.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.2063G>A	p.Arg688Gln	missense_variant	Exon 15 of 17	ENST00000645818.2	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1 link	c.2063G>A	p.Arg688Gln	missense_variant	Exon 15 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.1190G>A	p.Arg397Gln	missense_variant	Exon 10 of 13		XP_047290493.1
SPG7	XM_047434540.1 link	c.749G>A	p.Arg250Gln	missense_variant	Exon 7 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.2063G>A	p.Arg688Gln	missense_variant	Exon 15 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19841

AN:

152172

Hom.:

1646

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0355

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0852

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.148

AC:

36840

AN:

249596

AF XY:

0.152

show subpopulations

Gnomad AFR exome

AF:

0.0316

Gnomad AMR exome

AF:

0.0887

Gnomad ASJ exome

AF:

0.218

Gnomad EAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.0892

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.178

AC:

260547

AN:

1460152

Hom.:

24507

Cov.:

AF XY:

0.178

AC XY:

129313

AN XY:

726386

show subpopulations

African (AFR)

AF:

0.0284

AC:

949

AN:

33458

American (AMR)

AF:

0.0929

AC:

4153

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5720

AN:

26128

East Asian (EAS)

AF:

0.127

AC:

5024

AN:

39698

South Asian (SAS)

AF:

0.143

AC:

12368

AN:

86230

European-Finnish (FIN)

AF:

0.0951

AC:

4977

AN:

52350

Middle Eastern (MID)

AF:

0.180

AC:

971

AN:

5394

European-Non Finnish (NFE)

AF:

0.194

AC:

215748

AN:

1111832

Other (OTH)

AF:

0.176

AC:

10637

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

11798

23596

35393

47191

58989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.130

AC:

19833

AN:

152290

Hom.:

1644

Cov.:

AF XY:

0.126

AC XY:

9360

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0354

AC:

1473

AN:

41586

American (AMR)

AF:

0.120

AC:

1840

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

821

AN:

3472

East Asian (EAS)

AF:

0.145

AC:

748

AN:

5176

South Asian (SAS)

AF:

0.146

AC:

703

AN:

4828

European-Finnish (FIN)

AF:

0.0852

AC:

904

AN:

10616

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12663

AN:

67990

Other (OTH)

AF:

0.163

AC:

345

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

870

1739

2609

3478

4348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.174

Hom.:

4995

Bravo

AF:

0.128

TwinsUK

AF:

0.198

AC:

733

ALSPAC

AF:

0.203

AC:

784

ESP6500AA

AF:

0.0375

AC:

165

ESP6500EA

AF:

0.194

AC:

1667

ExAC

AF:

0.149

AC:

18099

Asia WGS

AF:

0.107

AC:

371

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.198

ClinVar

Significance: Benign

Submissions summary: Benign:9

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 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

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

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

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

PhyloP100

9.6

PrimateAI

Benign

0.47

REVEL

Uncertain

0.39

Polyphen

0.82

.;.;P;.;.;.;.;.;.

MPC

0.28

ClinPred

0.041

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.68

Mutation Taster

=53/47

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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NM_003119.4:c.2063G>A

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