16-89508418-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Moderate

The NM_003119.4(SPG7):​c.1A>T​(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 0.0000015 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 Likely pathogenic (★).

Frequency

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

Consequence

SPG7
NM_003119.4 initiator_codon

Scores

7
3
6

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

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 Likely_pathogenic. Variant got 8 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-T is Pathogenic according to our data. Variant chr16-89508418-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3242475.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000113
AC:
1
AN:
88730
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
50280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000313
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000150
AC:
2
AN:
1335614
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
658600
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:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:1
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

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.58
CADD
Benign
16
DANN
Benign
0.85
DEOGEN2
Benign
0.059
T;.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.010
Eigen_PC
Benign
-0.054
FATHMM_MKL
Uncertain
0.86
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
0.99
D
GERP RS
2.8
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