rs3803679

Positions:

• chr16-89524259-T-C

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.618+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,604,872 control chromosomes in the GnomAD database, including 165,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16468 hom., cov: 30)
  • Exomes 𝑓: 0.45 (149046 hom.)
• Consequence: SPG7 NM_003119.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.28

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=-0.93).
• BP6: Variant 16-89524259-T-C is Benign according to our data. Variant chr16-89524259-T-C is described in ClinVar as [Benign]. Clinvar id is 258910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89524259-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.618+12T>C		intron_variant		ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.618+12T>C		intron_variant			NM_003119.4	ENSP00000495795	P2

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70002 AN: 151138 Hom.: 16443 Cov.: 30

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.526

GnomAD3 exomes AF: 0.475 AC: 117836 AN: 247950 Hom.: 29032 AF XY: 0.484 AC XY: 64920 AN XY: 134270

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.448 AC: 651194 AN: 1453616 Hom.: 149046 Cov.: 47 AF XY: 0.453 AC XY: 327182 AN XY: 722100

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.689

Gnomad4 SAS exome AF: 0.560

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome AF: 0.463 AC: 70070 AN: 151256 Hom.: 16468 Cov.: 30 AF XY: 0.468 AC XY: 34558 AN XY: 73900

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.566

Gnomad4 FIN AF: 0.456

Gnomad4 NFE AF: 0.454

Gnomad4 OTH AF: 0.527

Alfa AF: 0.465 Hom.: 3055

Bravo AF: 0.461

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Mar 27, 2017	- -

not specified Benign:2

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+	-	- -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.086
DANN	Benign	0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs3803679; hg19: chr16-89590667;