dbSNP rs61755320: SPG7:p.Ala510Val (chr16-89546737-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM5PP3PP5BP4

The NM_003119.4(SPG7):c.1529C>T(p.Ala510Val) variant causes a missense change. The variant allele was found at a frequency of 0.0058 in 1,611,950 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000219172: Experimental studies have shown that this missense change affects SPG7 function (PMID:20186691)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A510L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 42 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:67U:1O:4

Conservation

PhyloP100: 4.97

Publications

112 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: G2P, Orphanet, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant optic atrophy
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPG7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000219172: Experimental studies have shown that this missense change affects SPG7 function (PMID: 20186691).; SCV000803517: "Functional assay shows a deleious effect." PMID:20186691; SCV001427239: Functional studies of this variant are supportive of a deleterious effect to the protein; however, the current available evidence is not sufficient to support a disease-causing effect (Bonn et al., 2010).; SCV002061281: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_moderate."; SCV002064525: Functional studies show p.Ala510Val impairs the function of the SPG7 protein (PMID: 20186691).; SCV002573329: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20186691)."; SCV003922888: At least one publication reports experimental evidence in a yeast complementation assay system that this missense change perturbs the proteotypic function of the hetero-oligomeric m-AAA protease (Bonn_2010).; SCV003930338: "functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product". PMID 20186691, PMID 32973427.; SCV004563041: Functional analyses have demonstrated impaired respiratory growth and proteolytic processing of MrpL32 in a yeast complementation assay (Bonn 2010).; SCV004812497: Complementation assays in yeast showed impaired respiratory growth indicating that this variant impacts protein function (PMID: 20186691).; SCV005397772: Studies in yeast and patient-derived stem cells indicate that this variant confers an increased expression of paraplegin and multiple mitochondrial dysfunctions (PMID: 32973427, 20186691).; SCV005399924: "This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant impairs protein function (PMID: 20186691)."; SCV000252339: Yeast expression studies found that the A510V variant perturbs the proteolytic function of paraplegin (Bonn et al., 2010); PMID: 20186691; SCV000399754: Bonn et al. (2010) conducted yeast complementation assays to study the activity of paraplegin variants identified in their study, and found that the p.Ala510Val variant demonstrated impaired proteolytic function in this assay.; SCV000221215: "Functional assays suggest the p.Ala510Val variant may lead to proteolytic deficiency (Bonn 2010 PMID: 20186691)"; SCV000742948: A yeast complementation assay demonstrated loss of proteolytic activity of the A510V mutant protein under certain conditions (Bonn, 2010).; SCV004118612: Functional characterization of SPG7 variants by a yeast complementation assay suggests that this variant impairs protein function (Bonn et al. 2010. PubMed ID: 20186691).

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89546736-GC-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 989124.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 16-89546737-C-T is Pathogenic according to our data. Variant chr16-89546737-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42016.

BP4

Computational evidence support a benign effect (MetaRNN=0.030638576). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.1529C>T	p.Ala510Val	missense	Exon 11 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.1529C>T	p.Ala510Val	missense	Exon 11 of 18	NP_001350779.1	A0A2R8Y3M4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.1529C>T	p.Ala510Val	missense	Exon 11 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.1508C>T	p.Ala503Val	missense	Exon 11 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000918773.1		c.1619C>T	p.Ala540Val	missense	Exon 11 of 17	ENSP00000588832.1

Frequencies

GnomAD3 genomes

AF:

0.00359

AC:

546

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00613

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00292

AC:

735

AN:

251478

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00495

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00603

AC:

8795

AN:

1459650

Hom.:

Cov.:

AF XY:

0.00578

AC XY:

4197

AN XY:

726296

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

33432

American (AMR)

AF:

0.00221

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000661

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00733

AC:

8141

AN:

1110008

Other (OTH)

AF:

0.00557

AC:

336

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

390

780

1171

1561

1951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.00359

AC:

547

AN:

152300

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41572

American (AMR)

AF:

0.00287

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00613

AC:

417

AN:

68032

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00474

Hom.:

Bravo

AF:

0.00371

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00252

AC:

306

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00594

EpiControl

AF:

0.00581

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 7 (46)

not provided (11)

Hereditary spastic paraplegia (4)

Dysarthria;C0037771:Spastic paraparesis;C0751837:Gait ataxia;C4551583:Cerebral cortical atrophy (1)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (1)

Hereditary ataxia (1)

Inborn genetic diseases (1)

Intellectual disability (1)

Optic nerve hypoplasia (1)

Optic neuropathy (1)

Retinal dystrophy (1)

Sensorimotor neuropathy;C1849156:Spastic ataxia (1)

Spastic Paraplegia, Recessive (1)

SPG7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.031

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PhyloP100

5.0

PrimateAI

Uncertain

0.54

REVEL

Pathogenic

0.92

Polyphen

1.0

MVP

0.97

MPC

0.78

ClinPred

0.018

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.78

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over