rs114854791

Positions:

chr16-89510526-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003119.4(SPG7):c.220G>A(p.Gly74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,607,286 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 0.00021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.69

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:

SPG7 (HGNC:):

SPG7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2433255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG7	NM_003119.4 linkuse as main transcript	c.220G>A	p.Gly74Arg	missense_variant	2/17	ENST00000645818.2	NP_003110.1	Q9UQ90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 linkuse as main transcript	c.220G>A	p.Gly74Arg	missense_variant	2/17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.000212

AC:

AN:

150732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00185

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

251020

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000618

AC:

AN:

1456438

Hom.:

Cov.:

AF XY:

0.0000635

AC XY:

AN XY:

724836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000381

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000641

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000212

AC:

AN:

150848

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

AN XY:

73584

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00185

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2014	p.Gly74Arg (GGG>AGG): c.220 G>A in exon 2 of the SPG7 gene (NM_003119.2). A variant of unknown significance has been identified in the SPG7 gene. The G74R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G74R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is mostly conserved across species; although, Arginine is present at this position in another species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). -

Hereditary spastic paraplegia 7

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2024

Variant summary: SPG7 c.220G>A (p.Gly74Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251020 control chromosomes. To our knowledge, no occurrence of c.220G>A in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 215213). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, 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

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

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

Eigen

Benign

0.14

Eigen_PC

Benign

0.034

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

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

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.24

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

.;M;.;.;.;.;.;.;.;.;M

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.7

.;.;.;.;D;.;.;.;.;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.071

.;.;.;.;T;.;.;.;.;D;D

Sift4G

Uncertain

0.027

.;.;.;.;.;.;.;.;.;D;D

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;D

Vest4

0.50, 0.49

MutPred

0.51

.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.96

MPC

0.28

ClinPred

0.58

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.47

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