Genetic Variant SPG7:p.Ala679Ala (chr16-89553894-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003119.4(SPG7):c.2037G>A(p.Ala679Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,086 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 74 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 64 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.98

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-89553894-G-A is Benign according to our data. Variant chr16-89553894-G-A is described in ClinVar as Benign. ClinVar VariationId is 139248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.98 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPG7	NM_003119.4	MANE Select	c.2037G>A	p.Ala679Ala	synonymous	Exon 15 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.2037G>A	p.Ala679Ala	synonymous	Exon 15 of 18	NP_001350779.1	A0A2R8Y3M4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.2037G>A	p.Ala679Ala	synonymous	Exon 15 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.2016G>A	p.Ala672Ala	synonymous	Exon 15 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000918773.1		c.2127G>A	p.Ala709Ala	synonymous	Exon 15 of 17	ENSP00000588832.1

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2470

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0567

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00419

AC:

1049

AN:

250424

AF XY:

0.00310

show subpopulations

Gnomad AFR exome

AF:

0.0551

Gnomad AMR exome

AF:

0.00338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00163

AC:

2376

AN:

1460730

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1027

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.0563

AC:

1883

AN:

33474

American (AMR)

AF:

0.00351

AC:

157

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52520

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1111830

Other (OTH)

AF:

0.00333

AC:

201

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

130

260

389

519

649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2485

AN:

152356

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1165

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0569

AC:

2364

AN:

41576

American (AMR)

AF:

0.00516

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68036

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

122

244

365

487

609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00669

Hom.:

Bravo

AF:

0.0185

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 7 (2)

not provided (2)

Hereditary spastic paraplegia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.5

(source)

DANN

Benign

0.55

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over