rs115999025

chr16-89532525-G-Achr16-89532525-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003119.4(SPG7):c.1213G>A(p.Val405Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,728 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3447649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.1213G>A	p.Val405Ile	missense_variant	9/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.1213G>A	p.Val405Ile	missense_variant	9/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000800 AC: 20 AN: 250076 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461412 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727006

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74482

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 0

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.1213G>A (p.V405I) alteration is located in exon 9 (coding exon 9) of the SPG7 gene. This alteration results from a G to A substitution at nucleotide position 1213, causing the valine (V) at amino acid position 405 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 405 of the SPG7 protein (p.Val405Ile). This variant is present in population databases (rs115999025, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. ClinVar contains an entry for this variant (Variation ID: 565650). 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 not expected to disrupt SPG7 protein function with a negative predictive value of 80%. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	24
Dann	Benign	0.96
Eigen	Benign	0.019
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.028	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		0.70, 0.56	.;.;P;.;.;.;.;.;P
Vest4		0.76
MutPred		0.56		.;.;Loss of phosphorylation at Y406 (P = 0.1458);Loss of phosphorylation at Y406 (P = 0.1458);Loss of phosphorylation at Y406 (P = 0.1458);Loss of phosphorylation at Y406 (P = 0.1458);Loss of phosphorylation at Y406 (P = 0.1458);.;Loss of phosphorylation at Y406 (P = 0.1458);
MVP		0.67
MPC		0.59
ClinPred		0.12	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.52

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

Other links and lift over

dbSNP: rs115999025; hg19: chr16-89598933; COSMIC: COSV99244796; COSMIC: COSV99244796;