Genetic Variant SPG7:p.Gly349Ser (chr16-89531961-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3PM1PP5_Very_StrongBS2_Supporting

The NM_003119.4(SPG7):c.1045G>A(p.Gly349Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,926 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000399749: Functional studies in yeast demonstrated that the variant results in impaired enzyme activity (Bonn et al. 2010)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G349V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:37

Conservation

PhyloP100: 9.65

Publications

28 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: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000399749: Functional studies in yeast demonstrated that the variant results in impaired enzyme activity (Bonn et al. 2010).; SCV000640067: Experimental studies have shown that this missense change affects SPG7 function (PMID: 20186691).; SCV002061286: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 20186691) - PS3_supporting."; SCV002503713: the missense change impairs proteolytic activity in a in vitro yeast complementation assay (PS3_Supporting; PMID: 20186691).; SCV002767383: Studies in mAAA protease-deficient yeast cells transfected with mutant human paraplegin, displayed impaired proteolytic enzyme activity (PMID: 20186691).; SCV004223527: At least one publication reports experimental evidence that this variant disrupts normal protein function (Bonn_2010).; SCV004564872: Functional analysis of this variant in a heterologous yeast assay suggests it fails to complement yeast similar to wildtype SPG7 (Bonn 2010). PMID: 20186691; SCV000252337: Functional studies performed in yeast cells found that G349S perturbs the function of the SPG7 protein (PMID: 20186691); SCV000844090: Experiment showed impaired ATPase activity (PMID:20186691).; SCV003593519: Functional studies in yeast showed that this alteration impairs enzyme activity (Bonn, 2010).; SCV005351518: Functional studies have shown that the p.Gly349Ser results in impaired enzyme activity in yeast cells (Bonn et al. 2010. PubMed ID: 20186691).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003119.4

PP5

Variant 16-89531961-G-A is Pathogenic according to our data. Variant chr16-89531961-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	NM_003119.4	MANE Select	c.1045G>A	p.Gly349Ser	missense	Exon 8 of 17	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1		c.1045G>A	p.Gly349Ser	missense	Exon 8 of 18	NP_001350779.1	A0A2R8Y3M4
SPG7	NM_199367.3		c.1045G>A	p.Gly349Ser	missense	Exon 8 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.1045G>A	p.Gly349Ser	missense	Exon 8 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.1024G>A	p.Gly342Ser	missense	Exon 8 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000341316.6	TSL:1	c.1045G>A	p.Gly349Ser	missense	Exon 8 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000834

AC:

209

AN:

250588

AF XY:

0.000796

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00165

AC:

2410

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1150

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33474

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.000243

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00206

AC:

2291

AN:

1111816

Other (OTH)

AF:

0.00106

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

136

272

407

543

679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.00101

AC:

154

AN:

152340

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41586

American (AMR)

AF:

0.00118

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00108

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 7 (24)

not provided (9)

Hereditary spastic paraplegia (1)

Inborn genetic diseases (1)

Retinal dystrophy (1)

SPG7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.78

MetaRNN

Uncertain

0.60

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.6

PhyloP100

9.7

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.96

MPC

0.79

ClinPred

0.49

GERP RS

5.8

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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