16-89508418-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_003119.4(SPG7):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000538 in 1,487,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

SPG7
NM_003119.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.65

Publications

13 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:

ENSG00000261118 (HGNC:):

ENSG00000261118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 89508547. Lost 0.054 part of the original CDS.

PS1

Another start lost variant in NM_003119.4 (SPG7) was described as [Likely_pathogenic] in ClinVar

PP5

Variant 16-89508418-A-G is Pathogenic according to our data. Variant chr16-89508418-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	NM_003119.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 18	NP_001350779.1	A0A2R8Y3M4
SPG7	NM_199367.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 10	NP_955399.1	Q9UQ90-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPG7	ENST00000645818.2	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000495795.2	Q9UQ90-1
SPG7	ENST00000268704.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000268704.3	A0A2U3TZH1
SPG7	ENST00000341316.6	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000341157.2	Q9UQ90-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00

AC:

AN:

88730

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000449

AC:

AN:

1335614

Hom.:

Cov.:

AF XY:

0.00000304

AC XY:

AN XY:

658600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26910

American (AMR)

AF:

0.00

AC:

AN:

29986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23568

East Asian (EAS)

AF:

0.00

AC:

AN:

30024

South Asian (SAS)

AF:

0.00

AC:

AN:

74624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3944

European-Non Finnish (NFE)

AF:

0.00000567

AC:

AN:

1057686

Other (OTH)

AF:

0.00

AC:

AN:

55494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67908

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 7 (3)

not provided (3)

SPG7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.061

Eigen

Benign

0.099

Eigen_PC

Benign

0.023

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.86

PhyloP100

1.7

PROVEAN

Benign

0.12

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.71

Vest4

0.67

MutPred

0.86

Gain of relative solvent accessibility (P = 0.0166)

MVP

0.95

ClinPred

0.99

GERP RS

2.8

PromoterAI

-0.68

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.90

gMVP

0.48

Mutation Taster

=9/191

disease causing (ClinVar)

(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