rs911119510

chr15-44663634-T-Cchr15-44663634-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025137.4(SPG11):c.14A>G(p.Glu5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,443,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. E5D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: -0.271

Genes affected

SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0668349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.14A>G	p.Glu5Gly	missense_variant	1/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.14A>G	p.Glu5Gly	missense_variant	1/40	1	NM_025137.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000624 AC: 9 AN: 1443058 Hom.: 0 Cov.: 32 AF XY: 0.00000557 AC XY: 4 AN XY: 717634

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 01, 2023	BP4, PM2 -

Hereditary spastic paraplegia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 5 of the SPG11 protein (p.Glu5Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 406524). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.14A>G (p.E5G) alteration is located in exon 1 (coding exon 1) of the SPG11 gene. This alteration results from a A to G substitution at nucleotide position 14, causing the glutamic acid (E) at amino acid position 5 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Amyotrophic lateral sclerosis type 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Charcot-Marie-Tooth disease axonal type 2X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	12
Dann	Benign	0.90
DEOGEN2	Benign	0.0095	T;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.61	T;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.85	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.059	T;T;T;T;T
Sift4G	Benign	0.085	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.16
MutPred		0.21		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.24
MPC		0.041
ClinPred		0.23	T
GERP RS		-6.6
Varity_R		0.064
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs911119510; hg19: chr15-44955832;