rs771130240

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_003119.4(SPG7):c.338A>G(p.Lys113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. K113K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.231

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027846336).

BP6

Variant 16-89512999-A-G is Benign according to our data. Variant chr16-89512999-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573952.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.338A>G	p.Lys113Arg	missense_variant	Exon 3 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.338A>G	p.Lys113Arg	missense_variant	Exon 3 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000101

AC:

AN:

248138

AF XY:

0.0000967

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460886

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.000515

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111248

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000782

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.338A>G (p.K113R) alteration is located in exon 3 (coding exon 3) of the SPG7 gene. This alteration results from a A to G substitution at nucleotide position 338, causing the lysine (K) at amino acid position 113 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 7

Benign:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

CADD

Benign

8.5

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.053

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.028

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

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.34

.;N;.;.;.;.;.;.;.;.;N

PhyloP100

-0.23

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.44

.;.;.;.;.;.;.;.;.;N;N

REVEL

Benign

0.076

Sift

Benign

0.21

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

Sift4G

Benign

0.22

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

Polyphen

0.094, 0.43

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

Vest4

0.13, 0.13

MutPred

0.27

.;Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);Loss of methylation at K113 (P = 0.0051);

MVP

0.64

MPC

0.17

ClinPred

0.029

GERP RS

-2.1

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.023

gMVP

0.22

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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rs771130240

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over