rs114135540

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_003119.4(SPG7):c.1083G>A(p.Ala361=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,613,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A361A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -5.47

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 16-89531999-G-A is Benign according to our data. Variant chr16-89531999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198782.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}.

BP7

Synonymous conserved (PhyloP=-5.47 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.1083G>A	p.Ala361=	synonymous_variant	8/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.1083G>A	p.Ala361=	synonymous_variant	8/17		NM_003119.4	P2	Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000371

AC:

AN:

250576

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00297

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000277

AC:

405

AN:

1461576

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00134

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000932

AC:

142

AN:

152360

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.00133

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Mar 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 02, 2015

- -

SPG7-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.35

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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