16-89553923-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003119.4(SPG7):​c.2066G>A​(p.Arg689His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,496 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

7
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.61
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPG7NM_003119.4 linkuse as main transcriptc.2066G>A p.Arg689His missense_variant 15/17 ENST00000645818.2 NP_003110.1
SPG7NM_001363850.1 linkuse as main transcriptc.2066G>A p.Arg689His missense_variant 15/18 NP_001350779.1
SPG7XM_047434537.1 linkuse as main transcriptc.1193G>A p.Arg398His missense_variant 10/13 XP_047290493.1
SPG7XM_047434540.1 linkuse as main transcriptc.752G>A p.Arg251His missense_variant 7/9 XP_047290496.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPG7ENST00000645818.2 linkuse as main transcriptc.2066G>A p.Arg689His missense_variant 15/17 NM_003119.4 ENSP00000495795 P2Q9UQ90-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000561
AC:
14
AN:
249356
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135256
show subpopulations
Gnomad AFR exome
AF:
0.000622
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1460138
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
726372
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152358
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2022In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 533738). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs148199060, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 689 of the SPG7 protein (p.Arg689His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.066
T
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
.;.;D;.;.;.;.;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Benign
1.9
.;.;M;.;.;.;.;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.59
T
REVEL
Pathogenic
0.79
Polyphen
1.0
.;.;D;.;.;.;.;.;.
MVP
0.82
MPC
0.86
ClinPred
0.49
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.65
gMVP
0.72

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: rs148199060; hg19: chr16-89620331; API