Genetic Variant SPG7:p.Ala2Ser (chr16-89508421-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003119.4(SPG7):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,014 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

SPG7
NM_003119.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.39

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:

ENSG00000261118 (HGNC:):

ENSG00000261118 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4 link	c.4G>T	p.Ala2Ser	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.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1338014

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

659790

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:

26968

American (AMR)

AF:

0.00

AC:

AN:

30426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23616

East Asian (EAS)

AF:

0.00

AC:

AN:

30264

South Asian (SAS)

AF:

0.00

AC:

AN:

74830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3950

European-Non Finnish (NFE)

AF:

9.44e-7

AC:

AN:

1058908

Other (OTH)

AF:

0.00

AC:

AN:

55634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

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

Eigen

Benign

0.11

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.45

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

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.59

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

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.1

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

PhyloP100

1.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.46

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

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.94

P;.;.;.;.;.;.;.;.;D

Vest4

0.31, 0.31

MutPred

0.29

Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);Gain of phosphorylation at A2 (P = 0.0399);

MVP

0.87

MPC

0.19

ClinPred

0.92

GERP RS

3.5

PromoterAI

-0.42

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.25

gMVP

0.48

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over