dbSNP rs2056309: SPG7:c.1325-3642G>A (chr16-89541006-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003119.4(SPG7):c.1325-3642G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 448,870 control chromosomes in the GnomAD database, including 15,468 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 15465 hom., cov: 29)

Exomes 𝑓: 0.000033 ( 3 hom. )

Consequence

SPG7
NM_003119.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.902

Publications

18 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.1325-3642G>A		intron_variant	Intron 9 of 16	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.1325-3642G>A		intron_variant	Intron 9 of 16		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

66923

AN:

147226

Hom.:

15456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.437

Gnomad AMR

AF:

0.454

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.629

Gnomad SAS

AF:

0.465

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.429

Gnomad OTH

AF:

0.513

GnomAD4 exome

AF:

0.0000332

AC:

AN:

301536

Hom.:

Cov.:

AF XY:

0.0000644

AC XY:

AN XY:

139646

show subpopulations

African (AFR)

AF:

0.000474

AC:

AN:

4218

American (AMR)

AF:

0.00

AC:

AN:

316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1446

East Asian (EAS)

AF:

0.00

AC:

AN:

438

South Asian (SAS)

AF:

0.00

AC:

AN:

4910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

346

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

280750

Other (OTH)

AF:

0.00

AC:

AN:

9038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.637

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.454

AC:

66946

AN:

147334

Hom.:

15465

Cov.:

AF XY:

0.455

AC XY:

32654

AN XY:

71708

show subpopulations

African (AFR)

AF:

0.479

AC:

19060

AN:

39790

American (AMR)

AF:

0.454

AC:

6688

AN:

14726

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

1564

AN:

3388

East Asian (EAS)

AF:

0.629

AC:

3152

AN:

5010

South Asian (SAS)

AF:

0.465

AC:

2120

AN:

4558

European-Finnish (FIN)

AF:

0.415

AC:

4153

AN:

10006

Middle Eastern (MID)

AF:

0.604

AC:

174

AN:

288

European-Non Finnish (NFE)

AF:

0.429

AC:

28607

AN:

66644

Other (OTH)

AF:

0.511

AC:

1039

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1848

3696

5543

7391

9239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.431

Hom.:

12874

Bravo

AF:

0.454

Asia WGS

AF:

0.437

AC:

1276

AN:

2918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_noAF

Benign

-0.94

CADD

Benign

1.1

(source)

DANN

Benign

0.73

PhyloP100

0.90

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over