rs140769107

chr16-89556980-G-Achr16-89556980-G-Cchr16-89556980-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003119.4(SPG7):c.2275G>A(p.Ala759Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: -0.0790

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022443116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.2275G>A	p.Ala759Thr	missense_variant	17/17	ENST00000645818.2
SPG7	XM_047434540.1	c.961G>A	p.Ala321Thr	missense_variant	9/9
SPG7	NM_001363850.1	c.*53G>A		3_prime_UTR_variant	18/18
SPG7	XM_047434537.1	c.*53G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.2275G>A	p.Ala759Thr	missense_variant	17/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000561 AC: 141 AN: 251324 Hom.: 0 AF XY: 0.000611 AC XY: 83 AN XY: 135880

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000977

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000805 AC: 1176 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.000776 AC XY: 564 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000985

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74472

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000800 Hom.: 1

Bravo AF: 0.000457

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2022	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in one individual with later onset spastic paraplegia who also carried a truncating variant in this gene (PMID: 21623769). -Computational tools predict that this variant is not damaging. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	SPG7: PM2:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2023	Reported as heterozygous variant in an individual with sporadic adult-onset pure spastic paraparesis; however, a second variant in SPG7 was not identified (Brugman et al., 2008); Reported with a pathogenic variant in a patient with adult-onset spastic paraplegia and ataxia, but it is not known if the variants occurred on the same (in cis) or on different (in trans) chromosomes (Schlipf et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18799786, 21623769) -

Hereditary spastic paraplegia 7 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	4.1
Dann	Benign	0.83
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;T;T;T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
Polyphen		0.021	.;.;B;.;.;.;.
MVP		0.52
MPC		0.20
ClinPred		0.016	T
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.32

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: rs140769107; hg19: chr16-89623388; COSMIC: COSV99244799; COSMIC: COSV99244799;