rs878854606

Positions:

• chr16-89530793-TGTGGATTATCTGAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003119.4(SPG7):​c.976_987+3delGATTATCTGAAGGTG​(p.Asp326_Lys329del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG7 NM_003119.4 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.90

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05234506 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 12, new splice context is: gagGTgtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89530793-TGTGGATTATCTGAAG-T is Pathogenic according to our data. Variant chr16-89530793-TGTGGATTATCTGAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	7/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	7/17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2020	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). ClinVar contains an entry for this variant (Variation ID: 239501). This variant, c.973_987del, results in the deletion of 5 amino acids of the SPG7 protein (p.Val325_Lys329del), but otherwise preserves the integrity of the reading frame. This variant also impacts the last nucleotide of exon 7 of the SPG7 coding sequence, which is part of the consensus splice site for this exon. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 2017	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854606; hg19: chr16-89597201;