rs771060044

Positions:

• chr16-89530719-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003119.4(SPG7):​c.898G>A​(p.Gly300Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4	c.898G>A	p.Gly300Arg	missense_variant	7/17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.898G>A	p.Gly300Arg	missense_variant	7/17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251496 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135922

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461874 Hom.: 0 Cov.: 47 AF XY: 0.0000124 AC XY: 9 AN XY: 727236

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2020

Identified as heterozygous by whole exome sequencing in a child with progressive motor neuron disease and also observed heterozygous in the individual's unaffected father and brother (Covone et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27406698) -

Hereditary spastic paraplegia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2018

This sequence change replaces glycine with arginine at codon 300 of the SPG7 protein (p.Gly300Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs771060044, ExAC 0.003%). This variant has been reported as heterozygous in an individual affected with progressive motor neuron disease. Biallelic variants in another autosomal recessive gene associated with this phenotype were also reported in this individual (PMID: 27406698). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L;.;.;.;.;.;.;.;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	.;.;.;.;.;.;.;.;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.43	.;.;.;.;.;.;.;.;.;T;T
Sift4G	Benign	0.54	.;.;.;.;.;.;.;.;.;T;T
Polyphen		0.80, 0.99	.;.;P;.;.;.;.;.;.;.;D
Vest4		0.85, 0.77
MutPred		0.49		.;.;Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);.;Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);
MVP		0.70
MPC		0.85
ClinPred		0.68	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs771060044; hg19: chr16-89597127;