16-89550579-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_StrongPM1PM2PP3_Moderate

The NM_003119.4(SPG7):c.1749G>T(p.Trp583Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.91

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS1

Transcript NM_003119.4 (SPG7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 6820

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003119.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.1749G>T	p.Trp583Cys	missense_variant	Exon 13 of 17	ENST00000645818.2	NP_003110.1	Q9UQ90-1
SPG7	NM_001363850.1 link	c.1749G>T	p.Trp583Cys	missense_variant	Exon 13 of 18		NP_001350779.1
SPG7	XM_047434537.1 link	c.876G>T	p.Trp292Cys	missense_variant	Exon 8 of 13		XP_047290493.1
SPG7	XM_047434540.1 link	c.435G>T	p.Trp145Cys	missense_variant	Exon 5 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.1749G>T	p.Trp583Cys	missense_variant	Exon 13 of 17		NM_003119.4	ENSP00000495795.2		Q9UQ90-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60380

⚠️ 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

.;.;D;.;.;.;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.5

.;.;M;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Uncertain

0.76

REVEL

Pathogenic

0.75

Polyphen

1.0

.;.;D;.;.;.;.;.;.

MutPred

0.51

.;.;Loss of stability (P = 0.1225);.;.;Loss of stability (P = 0.1225);Loss of stability (P = 0.1225);.;.;

MVP

0.97

MPC

1.0

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.97

gMVP

0.89

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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16-89550579-G-T

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