16-89553932-G-C

Variant names:

• chr16-89553932-G-C
• rs121918357
• NM_003119.4:c.2075G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003119.4(SPG7):​c.2075G>C​(p.Ser692Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S692G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.67
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_003119.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-89553932-G-C is Pathogenic according to our data. Variant chr16-89553932-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6815.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPG7	NM_003119.4	c.2075G>C	p.Ser692Thr	missense_variant	Exon 15 of 17	ENST00000645818.2	NP_003110.1
SPG7	NM_001363850.1	c.2075G>C	p.Ser692Thr	missense_variant	Exon 15 of 18		NP_001350779.1
SPG7	XM_047434537.1	c.1202G>C	p.Ser401Thr	missense_variant	Exon 10 of 13		XP_047290493.1
SPG7	XM_047434540.1	c.761G>C	p.Ser254Thr	missense_variant	Exon 7 of 9		XP_047290496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPG7	ENST00000645818.2	c.2075G>C	p.Ser692Thr	missense_variant	Exon 15 of 17		NM_003119.4	ENSP00000495795.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 7 Pathogenic:2

Jul 24, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Uncertain	0.54	T
REVEL	Pathogenic	0.94
Polyphen		1.0	.;.;D;.;.;.;.;.;.
MutPred		0.93		.;.;Gain of phosphorylation at S692 (P = 0.0535);.;.;.;Gain of phosphorylation at S692 (P = 0.0535);.;.;
MVP		0.95
MPC		0.74
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.86
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918357; hg19: chr16-89620340;