rs794726906

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong

The NM_003119.4(SPG7):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000599 in 1,335,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

SPG7
NM_003119.4 initiator_codon

Scores

7
3
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.65
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 129 CDS bases. Genomic position: 89508546. Lost 0.054 part of the original CDS.
PS1
Another start lost variant in NM_003119.4 (SPG7) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-89508418-A-C is Pathogenic according to our data. Variant chr16-89508418-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3236318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPG7NM_003119.4 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 17 ENST00000645818.2 NP_003110.1 Q9UQ90-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPG7ENST00000645818.2 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 17 NM_003119.4 ENSP00000495795.2 Q9UQ90-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000338
AC:
3
AN:
88730
Hom.:
0
AF XY:
0.0000398
AC XY:
2
AN XY:
50280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000109
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000378
GnomAD4 exome
AF:
0.00000599
AC:
8
AN:
1335614
Hom.:
0
Cov.:
31
AF XY:
0.00000607
AC XY:
4
AN XY:
658600
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000667
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000284
Gnomad4 OTH exome
AF:
0.0000541
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000471
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jun 11, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.58
CADD
Benign
17
DANN
Benign
0.84
DEOGEN2
Benign
0.059
T;.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.010
Eigen_PC
Benign
-0.054
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
PROVEAN
Benign
0.32
.;.;.;N;.;.;.;.;N;N
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
.;.;.;D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0
.;.;.;.;.;.;.;.;D;D
Polyphen
0.52
P;.;.;.;.;.;.;.;.;P
Vest4
0.63, 0.61
MutPred
0.91
Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);Gain of stability (P = 0.2061);
MVP
0.88
ClinPred
0.98
D
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.93
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs794726906; hg19: chr16-89574826; API