rs2292954

Positions:

• chr16-89546715-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1673 hom., cov: 31)
  • Exomes 𝑓: 0.18 (24659 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.86

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]

ACMG classification

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	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	c.1507A>G	p.Thr503Ala	missense_variant	11/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19881 AN: 151904 Hom.: 1675 Cov.: 31

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

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.: 32 AF XY: 0.179 AC XY: 129777 AN XY: 726748

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.: 31 AF XY: 0.126 AC XY: 9371 AN XY: 74298

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

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

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.88	D
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	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
Polyphen		0.0	.;.;B;.;.;.;.;.;.
MPC		0.20
ClinPred		0.0073	T
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

Other links and lift over

dbSNP: rs2292954; hg19: chr16-89613123; COSMIC: COSV51952248; COSMIC: COSV51952248;