rs535030441

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_003119.4(SPG7):c.4G>A(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,490,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 1.39

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034443736).

BP6

Variant 16-89508421-G-A is Benign according to our data. Variant chr16-89508421-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215198.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	1/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	1/17		NM_003119.4	P2	Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

189

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000731

AC:

AN:

90242

Hom.:

AF XY:

0.000627

AC XY:

AN XY:

51012

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000584

Gnomad OTH exome

AF:

0.000371

GnomAD4 exome

AF:

0.000739

AC:

989

AN:

1338014

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

471

AN XY:

659790

show subpopulations

Gnomad4 AFR exome

AF:

0.00315

Gnomad4 AMR exome

AF:

0.00194

Gnomad4 ASJ exome

AF:

0.0000423

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000267

Gnomad4 FIN exome

AF:

0.000180

Gnomad4 NFE exome

AF:

0.000740

Gnomad4 OTH exome

AF:

0.000935

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152212

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000221

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2023	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). Computational tools predict that this variant is not damaging. The variant is located in a region that is considered important for protein function and/or structure. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 16534102, 20301286) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Hereditary spastic paraplegia 7

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 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. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2019

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.052

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

Eigen

Benign

0.071

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.49

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

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.034

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

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

0.99

N;N

PrimateAI

Pathogenic

0.86

Polyphen

0.89

P;.;.;.;.;.;.;.;.;D

Vest4

0.28, 0.29

MVP

0.88

MPC

0.20

ClinPred

0.16

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.25

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over