rs878854606

chr16-89530793-TGTGGATTATCTGAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The NM_003119.4(SPG7):c.976_987+3del variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG7 NM_003119.4 inframe_deletion, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003119.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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	UniProt
SPG7	NM_003119.4	c.976_987+3del		inframe_deletion, splice_region_variant	7/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.976_987+3del		inframe_deletion, splice_region_variant	7/17		NM_003119.4	P2

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

Hereditary spastic paraplegia 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

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;