16-89546731-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP4

The NM_003119.4(SPG7):​c.1523G>A​(p.Arg508His) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R508C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

7
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.93

Publications

1 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_003119.4
BP4
Computational evidence support a benign effect (MetaRNN=0.29778096).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPG7NM_003119.4 linkc.1523G>A p.Arg508His missense_variant Exon 11 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.1523G>A p.Arg508His missense_variant Exon 11 of 17 NM_003119.4 ENSP00000495795.2 Q9UQ90-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000756
AC:
19
AN:
251476
AF XY:
0.0000809
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000326
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000411
AC:
60
AN:
1460896
Hom.:
0
Cov.:
32
AF XY:
0.0000413
AC XY:
30
AN XY:
726830
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33458
American (AMR)
AF:
0.0000671
AC:
3
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.000277
AC:
11
AN:
39692
South Asian (SAS)
AF:
0.000162
AC:
14
AN:
86242
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000234
AC:
26
AN:
1111150
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60352
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.472
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152296
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74470
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41568
American (AMR)
AF:
0.0000653
AC:
1
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000387
AC:
2
AN:
5170
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.445
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000576
AC:
7

ClinVar

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

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1
Apr 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary spastic paraplegia 7 Uncertain:1
Jul 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 508 of the SPG7 protein (p.Arg508His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27217339). ClinVar contains an entry for this variant (Variation ID: 570831). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;.;T;.;.;.;.;.;.
Eigen
Benign
0.044
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.30
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.6
.;.;L;.;.;.;.;.;.
PhyloP100
3.9
PrimateAI
Benign
0.44
T
REVEL
Uncertain
0.38
Polyphen
0.58
.;.;P;.;.;.;.;.;.
MutPred
0.58
.;.;Loss of methylation at R508 (P = 0.0578);Loss of methylation at R508 (P = 0.0578);.;Loss of methylation at R508 (P = 0.0578);Loss of methylation at R508 (P = 0.0578);.;.;
MVP
0.84
MPC
0.28
ClinPred
0.12
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.42
gMVP
0.61
Mutation Taster
=22/78
disease causing

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

Other links and lift over

dbSNP: rs201733920; hg19: chr16-89613139; COSMIC: COSV107277073; COSMIC: COSV107277073; API