rs111475461

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_003119.4(SPG7):c.1457G>A(p.Arg486Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00806 in 1,610,872 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0083 ( 71 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 2.52

Publications

13 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: Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009461194).

BP6

Variant 16-89546665-G-A is Benign according to our data. Variant chr16-89546665-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139241.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00537 (816/152030) while in subpopulation NFE AF = 0.00979 (665/67914). AF 95% confidence interval is 0.00918. There are 2 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.1457G>A	p.Arg486Gln	missense_variant	Exon 11 of 17	ENST00000645818.2	NP_003110.1	Q9UQ90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.1457G>A	p.Arg486Gln	missense_variant	Exon 11 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

817

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.000851

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00979

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00466

AC:

1145

AN:

245470

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000934

Gnomad NFE exome

AF:

0.00862

Gnomad OTH exome

AF:

0.00531

GnomAD4 exome

AF:

0.00834

AC:

12172

AN:

1458842

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

5946

AN XY:

725850

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33450

American (AMR)

AF:

0.00244

AC:

109

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00137

AC:

118

AN:

86214

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0103

AC:

11470

AN:

1109274

Other (OTH)

AF:

0.00564

AC:

340

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

511

1022

1533

2044

2555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.00537

AC:

816

AN:

152030

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

360

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41504

American (AMR)

AF:

0.00406

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000851

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00979

AC:

665

AN:

67914

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00814

Hom.:

Bravo

AF:

0.00527

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00431

AC:

523

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Uncertain:1Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Aug 29, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 12, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Apr 04, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG7: PM5, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0095

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.3

.;.;L;.;.;.;.;.;.

PhyloP100

2.5

PrimateAI

Benign

0.38

REVEL

Benign

0.28

Polyphen

0.077

.;.;B;.;.;.;.;.;.

MVP

0.82

MPC

0.25

ClinPred

0.0098

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.48

Mutation Taster

=77/23

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over