16-89524042-A-C

Position:

• chr16-89524042-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003119.4(SPG7):​c.413A>C​(p.Tyr138Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,260 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y138N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SPG7 NM_003119.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG7	NM_003119.4	c.413A>C	p.Tyr138Ser	missense_variant	4/17	ENST00000645818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG7	ENST00000645818.2	c.413A>C	p.Tyr138Ser	missense_variant	4/17		NM_003119.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SPG7-related disease. ClinVar contains an entry for this variant (Variation ID: 215203). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 138 of the SPG7 protein (p.Tyr138Ser). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and serine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2020

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	.;.;.;.;.;.;.;.;.;N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.039	.;.;.;.;.;.;.;.;.;D;T
Sift4G	Benign	0.35	.;.;.;.;.;.;.;.;.;T;T
Polyphen		0.65, 0.96	.;.;P;.;.;.;.;.;.;.;D
Vest4		0.65, 0.67
MVP		0.97
MPC		0.66
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.40
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs377268309; hg19: chr16-89590450;