NM_003119.4:c.2280G>A

Variant names:

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.2280G>A(p.Pro760Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,613,870 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 32)

Exomes 𝑓: 0.013 ( 144 hom. )

Consequence

SPG7
NM_003119.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.03

Publications

8 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 16-89556985-G-A is Benign according to our data. Variant chr16-89556985-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0104 (1579/152306) while in subpopulation EAS AF = 0.0178 (92/5176). AF 95% confidence interval is 0.0148. There are 14 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SPG7	NM_003119.4 link	c.2280G>A	p.Pro760Pro	synonymous_variant	Exon 17 of 17	ENST00000645818.2	NP_003110.1
SPG7	XM_047434540.1 link	c.966G>A	p.Pro322Pro	synonymous_variant	Exon 9 of 9		XP_047290496.1
SPG7	NM_001363850.1 link	c.*58G>A		3_prime_UTR_variant	Exon 18 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.*58G>A		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.2280G>A	p.Pro760Pro	synonymous_variant	Exon 17 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1577

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.00814

GnomAD2 exomes

AF:

0.0126

AC:

3159

AN:

251310

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0178

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.0150

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0133

AC:

19375

AN:

1461564

Hom.:

144

Cov.:

AF XY:

0.0130

AC XY:

9456

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

33472

American (AMR)

AF:

0.0118

AC:

529

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00727

AC:

190

AN:

26136

East Asian (EAS)

AF:

0.0209

AC:

830

AN:

39700

South Asian (SAS)

AF:

0.00684

AC:

590

AN:

86256

European-Finnish (FIN)

AF:

0.0143

AC:

762

AN:

53296

Middle Eastern (MID)

AF:

0.00576

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0140

AC:

15611

AN:

1111862

Other (OTH)

AF:

0.0127

AC:

767

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1086

2172

3259

4345

5431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.0104

AC:

1579

AN:

152306

Hom.:

Cov.:

AF XY:

0.00998

AC XY:

743

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41560

American (AMR)

AF:

0.00549

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.0178

AC:

AN:

5176

South Asian (SAS)

AF:

0.00642

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1026

AN:

68034

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0135

Hom.:

Bravo

AF:

0.00910

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 7

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 03, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Nov 20, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.45

(source)

DANN

Benign

0.82

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over