rs1555445707

Positions:

• chr15-44563200-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000261866.12(SPG11):​c.7253A>G​(p.His2418Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H2418H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPG11 ENST00000261866.12 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.7253A>G	p.His2418Arg	missense_variant	40/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.7253A>G	p.His2418Arg	missense_variant	40/40	1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.7253A>G(p.His2418Arg) variant in SPG11 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.His2418Arg variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance. he amino acid change p.His2418Arg in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 2418 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	This sequence change replaces histidine with arginine at codon 2418 of the SPG11 protein (p.His2418Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. 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: "Possibly Damaging"; 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.00080	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.88	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.98	D;.
Vest4		0.57
MutPred		0.39		Loss of sheet (P = 0.0142);.;
MVP		0.82
MPC		0.19
ClinPred		0.77	D
GERP RS		6.0
Varity_R		0.078
gMVP		0.43

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: rs1555445707; hg19: chr15-44855398;