dbSNP rs61747711: SPG7:p.Ile764Ile (chr16-89556997-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003119.4(SPG7):c.2292C>T(p.Ile764Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,613,830 control chromosomes in the GnomAD database, including 1,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 93 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1184 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.20

Publications

6 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=-0.77).

BP6

Variant 16-89556997-C-T is Benign according to our data. Variant chr16-89556997-C-T is described in ClinVar as Benign. ClinVar VariationId is 139250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.2 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0281 (4274/152306) while in subpopulation NFE AF = 0.0409 (2781/68014). AF 95% confidence interval is 0.0396. There are 93 homozygotes in GnomAd4. There are 1970 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 93 AR,AD gene

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.2292C>T	p.Ile764Ile	synonymous	Exon 17 of 17	NP_003110.1	Q9UQ90-1
	SPG7	NM_001363850.1		c.*70C>T		3_prime_UTR	Exon 18 of 18	NP_001350779.1	A0A2R8Y3M4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.2292C>T	p.Ile764Ile	synonymous	Exon 17 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.2271C>T	p.Ile757Ile	synonymous	Exon 17 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000918773.1		c.2382C>T	p.Ile794Ile	synonymous	Exon 17 of 17	ENSP00000588832.1

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4276

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0923

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.0798

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0409

Gnomad OTH

AF:

0.0406

GnomAD2 exomes

AF:

0.0287

AC:

7212

AN:

251238

AF XY:

0.0292

show subpopulations

Gnomad AFR exome

AF:

0.00843

Gnomad AMR exome

AF:

0.0188

Gnomad ASJ exome

AF:

0.0615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.0436

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0378

AC:

55173

AN:

1461524

Hom.:

1184

Cov.:

AF XY:

0.0368

AC XY:

26774

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00932

AC:

312

AN:

33474

American (AMR)

AF:

0.0193

AC:

865

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

1688

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00883

AC:

762

AN:

86254

European-Finnish (FIN)

AF:

0.0187

AC:

996

AN:

53260

Middle Eastern (MID)

AF:

0.0322

AC:

183

AN:

5676

European-Non Finnish (NFE)

AF:

0.0433

AC:

48137

AN:

1111934

Other (OTH)

AF:

0.0369

AC:

2230

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2956

5913

8869

11826

14782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1780

3560

5340

7120

8900

<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:

0.0281

AC:

4274

AN:

152306

Hom.:

Cov.:

AF XY:

0.0265

AC XY:

1970

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41578

American (AMR)

AF:

0.0239

AC:

366

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0798

AC:

277

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00974

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10624

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0409

AC:

2781

AN:

68014

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

210

420

630

840

1050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0374

Hom.:

338

Bravo

AF:

0.0289

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0450

EpiControl

AF:

0.0420

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)

not specified (2)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.043

(source)

DANN

Benign

0.87

PhyloP100

-2.2

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