rs80324518

Positions:

• chr16-89548126-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003119.4(SPG7):​c.1663+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 1,579,268 control chromosomes in the GnomAD database, including 5,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (292 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5291 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.733

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-89548126-C-T is Benign according to our data. Variant chr16-89548126-C-T is described in ClinVar as [Benign]. Clinvar id is 139242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89548126-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.1663+13C>T		intron_variant		ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.1663+13C>T		intron_variant			NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8196 AN: 152212 Hom.: 292 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.0464

GnomAD3 exomes AF: 0.0537 AC: 12881 AN: 239650 Hom.: 481 AF XY: 0.0541 AC XY: 7081 AN XY: 130822

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0605

Gnomad EAS exome AF: 0.000219

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0892

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0796 AC: 113564 AN: 1426938 Hom.: 5291 Cov.: 26 AF XY: 0.0776 AC XY: 55231 AN XY: 711702

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0573

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.00885

Gnomad4 FIN exome AF: 0.0696

Gnomad4 NFE exome AF: 0.0946

Gnomad4 OTH exome AF: 0.0642

GnomAD4 genome AF: 0.0538 AC: 8196 AN: 152330 Hom.: 292 Cov.: 33 AF XY: 0.0508 AC XY: 3784 AN XY: 74500

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.0645

Gnomad4 NFE AF: 0.0878

Gnomad4 OTH AF: 0.0459

Alfa AF: 0.0712 Hom.: 83

Bravo AF: 0.0494

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 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 provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.27
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs80324518; hg19: chr16-89614534;