rs12960

Positions:

chr16-89553920-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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 (★★).

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

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:

SPG7 (HGNC:):

SPG7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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. Variant chr16-89553920-G-A 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	Protein	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.2063G>A	p.Arg688Gln	missense_variant	15/17	ENST00000645818.2	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1 linkuse as main transcript	c.2063G>A	p.Arg688Gln	missense_variant	15/18		NP_001350779.1
SPG7	XM_047434537.1 linkuse as main transcript	c.1190G>A	p.Arg397Gln	missense_variant	10/13		XP_047290493.1
SPG7	XM_047434540.1 linkuse as main transcript	c.749G>A	p.Arg250Gln	missense_variant	7/9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.2063G>A	p.Arg688Gln	missense_variant	15/17		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

GnomAD3 exomes

AF:

0.148

AC:

36840

AN:

249596

Hom.:

3105

AF XY:

0.152

AC XY:

20541

AN XY:

135350

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 SAS exome

AF:

0.138

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

Gnomad4 AFR exome

AF:

0.0284

Gnomad4 AMR exome

AF:

0.0929

Gnomad4 ASJ exome

AF:

0.219

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.0951

Gnomad4 NFE exome

AF:

0.194

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.130

AC:

19833

AN:

152290

Hom.:

1644

Cov.:

AF XY:

0.126

AC XY:

9360

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0354

Gnomad4 AMR

AF:

0.120

Gnomad4 ASJ

AF:

0.236

Gnomad4 EAS

AF:

0.145

Gnomad4 SAS

AF:

0.146

Gnomad4 FIN

AF:

0.0852

Gnomad4 NFE

AF:

0.186

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.178

Hom.:

3478

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

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	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:2

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

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

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

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

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

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