NM_003119.4:c.53G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003119.4(SPG7):c.53G>T(p.Gly18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000265 in 1,508,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18S) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Publications

1 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:

ENSG00000261118 (HGNC:):

ENSG00000261118 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22446704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.53G>T	p.Gly18Val	missense_variant	Exon 1 of 17	ENST00000645818.2	NP_003110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2 link	c.53G>T	p.Gly18Val	missense_variant	Exon 1 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152054

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1356252

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

669032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27622

American (AMR)

AF:

0.00

AC:

AN:

33460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24122

East Asian (EAS)

AF:

0.00

AC:

AN:

32220

South Asian (SAS)

AF:

0.00

AC:

AN:

76506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4006

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1067508

Other (OTH)

AF:

0.00

AC:

AN:

56572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.070

T;.;.;.;.;.;.;.;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.59

T;T;T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.1

L;.;.;.;.;.;.;.;.;L

PhyloP100

1.1

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.99

.;.;.;.;.;.;.;.;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.016

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

Sift4G

Uncertain

0.051

.;.;.;.;.;.;.;.;T;D

Polyphen

0.28

B;.;.;.;.;.;.;.;.;P

Vest4

0.28, 0.27

MutPred

0.17

Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);Loss of glycosylation at P17 (P = 0.0604);

MVP

0.71

MPC

0.26

ClinPred

0.19

GERP RS

0.68

PromoterAI

0.024

Neutral

(source)

Varity_R

0.095

gMVP

0.29

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