NM_003119.4:c.976_987+3delGATTATCTGAAGGTG

Variant names:

• chr16-89530793-TGTGGATTATCTGAAG-T
• rs878854606
• NM_003119.4:c.976_987+3delGATTATCTGAAGGTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05276382 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.
• PP5: Variant 16-89530793-TGTGGATTATCTGAAG-T is Pathogenic according to our data. Variant chr16-89530793-TGTGGATTATCTGAAG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 239501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 17	NP_003110.1
	SPG7	NM_001363850.1		c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 18	NP_001350779.1
	SPG7	NM_199367.3		c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 10	NP_955399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	ENST00000645818.2	MANE Select	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 17	ENSP00000495795.2
	SPG7	ENST00000268704.7	TSL:1	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 17	ENSP00000268704.3
	SPG7	ENST00000341316.6	TSL:1	c.976_987+3delGATTATCTGAAGGTG	p.Asp326_Lys329del	splice_donor conservative_inframe_deletion splice_region intron	Exon 7 of 10	ENSP00000341157.2

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 02, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 30, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia 7 Pathogenic:2

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs878854606; hg19: chr16-89597201;