dbSNP rs1188029212: SPG7:p.Leu7Met (chr16-89508436-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003119.4(SPG7):c.19C>A(p.Leu7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.517

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: G2P, Orphanet, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
autosomal dominant optic atrophy
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPG7 links:

ENSG00000261118 (HGNC:):

ENSG00000261118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32501784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	NM_003119.4	MANE Select	c.19C>A	p.Leu7Met	missense	Exon 1 of 17	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1		c.19C>A	p.Leu7Met	missense	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
SPG7	NM_199367.3		c.19C>A	p.Leu7Met	missense	Exon 1 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.19C>A	p.Leu7Met	missense	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.19C>A	p.Leu7Met	missense	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000341316.6	TSL:1	c.19C>A	p.Leu7Met	missense	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1346454

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

664022

African (AFR)

AF:

0.00

AC:

AN:

27188

American (AMR)

AF:

0.00

AC:

AN:

31934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23838

East Asian (EAS)

AF:

0.00

AC:

AN:

31156

South Asian (SAS)

AF:

0.00

AC:

AN:

75578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062990

Other (OTH)

AF:

0.00

AC:

AN:

56082

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.063

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.35

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.0

PhyloP100

0.52

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.040

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.40

MutPred

0.45

Gain of MoRF binding (P = 0.1373)

MVP

0.69

MPC

0.20

ClinPred

0.54

GERP RS

0.78

PromoterAI

-0.24

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.15

gMVP

0.36

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over