rs2292954

Positions:

chr16-89546715-A-G

Variant summary

Our verdict is Benign. Variant got -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. 12/18 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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, 3 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 id is 130369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89546715-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.1507A>G	p.Thr503Ala	missense_variant	11/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.1507A>G	p.Thr503Ala	missense_variant	11/17		NM_003119.4	P2	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

GnomAD3 exomes

AF:

0.149

AC:

37389

AN:

251458

Hom.:

3177

AF XY:

0.153

AC XY:

20774

AN XY:

135906

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 SAS exome

AF:

0.139

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

Gnomad4 AFR exome

AF:

0.0286

Gnomad4 AMR exome

AF:

0.0930

Gnomad4 ASJ exome

AF:

0.221

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.144

Gnomad4 FIN exome

AF:

0.0962

Gnomad4 NFE exome

AF:

0.195

Gnomad4 OTH exome

AF:

0.177

GnomAD4 genome

AF:

0.131

AC:

19872

AN:

152022

Hom.:

1673

Cov.:

AF XY:

0.126

AC XY:

9371

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0356

Gnomad4 AMR

AF:

0.121

Gnomad4 ASJ

AF:

0.239

Gnomad4 EAS

AF:

0.144

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.0853

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.182

Hom.:

6733

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2018	Allele frequency 14% of total chromosomes by gnomad (http://gnomad.broadinstitut e.org). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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

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;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over