chr16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_003119.4(SPG7):c.618+11_618+68delGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGAGAGTGAGG variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,608,672 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 30)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

SPG7
NM_003119.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.46

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: Benign. The variant received -11 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T is Benign according to our data. Variant chr16-89524249-TGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.618+11_618+68delGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGAGAGTGAGG		intron_variant	Intron 4 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.618+3_618+60delGAGTGAGGGTGCGGGAGGCCTGTGAGTGAGGGTGTGGGCACAGGCTGGCAGCCTGTGA		splice_region_variant, intron_variant	Intron 4 of 16		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

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:

0.00144

GnomAD2 exomes

AF:

0.000582

AC:

145

AN:

249300

AF XY:

0.000378

show subpopulations

Gnomad AFR exome

AF:

0.00871

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000235

AC:

342

AN:

1456802

Hom.:

AF XY:

0.000207

AC XY:

150

AN XY:

724144

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00854

AC:

285

AN:

33372

American (AMR)

AF:

0.000179

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52736

Middle Eastern (MID)

AF:

0.000416

AC:

AN:

4802

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109348

Other (OTH)

AF:

0.000682

AC:

AN:

60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.359

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00210

AC:

319

AN:

151870

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

150

AN XY:

74244

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00746

AC:

309

AN:

41402

American (AMR)

AF:

0.000459

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67930

Other (OTH)

AF:

0.00143

AC:

AN:

2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000843

Hom.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22964162) -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPG7: BS2 -

Hereditary spastic paraplegia 7

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.5

Mutation Taster

=61/39

polymorphism

(source)

Splicing

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