16-89557070-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_003119.4(SPG7):c.2365G>T(p.Glu789*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SPG7
NM_003119.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.91

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: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00963 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.2365G>T	p.Glu789*	stop_gained	Exon 17 of 17	ENST00000645818.2	NP_003110.1	Q9UQ90-1
SPG7	XM_047434540.1 link	c.1051G>T	p.Glu351*	stop_gained	Exon 9 of 9		XP_047290496.1
SPG7	NM_001363850.1 link	c.*143G>T		3_prime_UTR_variant	Exon 18 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.*143G>T		3_prime_UTR_variant	Exon 13 of 13		XP_047290493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.2365G>T	p.Glu789*	stop_gained	Exon 17 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459474

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726014

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111938

Other (OTH)

AF:

0.0000166

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SPG7 c.2365G>T (p.Glu789X) results in a premature termination codon, predicted to cause a truncation of the encoded protein that is not anticipated to result in nonsense mediated decay. Variants downstream of this position have not been classified as pathogenic. The variant was absent in 249510 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2365G>T in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia 7

Uncertain:1

May 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1510535). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs372033226, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu789*) in the SPG7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the SPG7 protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.052

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.80

PhyloP100

1.9

GERP RS

-0.71

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

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16-89557070-G-T

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