16-89508420-G-A

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.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,348 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SPG7
NM_003119.4 start_lost

Scores

8
3
5

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.39
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]

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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 16-89508420-G-A is Pathogenic according to our data. Variant chr16-89508420-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3242469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89508420-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPG7NM_003119.4 linkc.3G>A p.Met1? start_lost 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.3G>A p.Met1? start_lost Exon 1 of 17 NM_003119.4 ENSP00000495795.2 Q9UQ90-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000150
AC:
2
AN:
1337348
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
659468
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
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: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

May 01, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SPG7: PM2, PM3, PS1:Moderate, PVS1:Moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.62
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.061
T;.;.;T;.;.;.;.;.;.
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
PROVEAN
Benign
0.17
.;.;.;N;.;.;.;.;N;N
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
.;.;.;D;.;.;.;.;D;D
Sift4G
Pathogenic
0.0
.;.;.;.;.;.;.;.;D;D
Polyphen
0.85
P;.;.;.;.;.;.;.;.;P
Vest4
0.70, 0.70
MutPred
0.84
Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);Loss of disorder (P = 0.0758);
MVP
0.96
ClinPred
1.0
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.96
gMVP
0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89574828; API