rs145643238

Positions:

• chr15-44585636-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_Strong BS1_Supporting BS2

The NM_025137.4(SPG11):​c.5121G>T​(p.Glu1707Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000764 in 1,559,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: SPG11 NM_025137.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:1 O:1
• Conservation: PhyloP100: 5.98

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 -1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00096 (145/150986) while in subpopulation AMR AF= 0.00463 (70/15122). AF 95% confidence interval is 0.00376. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4	c.5121G>T	p.Glu1707Asp	missense_variant, splice_region_variant	29/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12	c.5121G>T	p.Glu1707Asp	missense_variant, splice_region_variant	29/40	1	NM_025137.4	ENSP00000261866

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 145 AN: 150880 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000767

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.000688 AC: 172 AN: 249886 Hom.: 0 AF XY: 0.000732 AC XY: 99 AN XY: 135222

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000883

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000737

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000743 AC: 1046 AN: 1408214 Hom.: 2 Cov.: 32 AF XY: 0.000727 AC XY: 511 AN XY: 702746

Gnomad4 AFR exome AF: 0.000156

Gnomad4 AMR exome AF: 0.000944

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000833

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.000776

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.000960 AC: 145 AN: 150986 Hom.: 0 Cov.: 30 AF XY: 0.00115 AC XY: 85 AN XY: 73762

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00463

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00109

Gnomad4 NFE AF: 0.000767

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:9

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2024	Reported previously in an individual with Parkinson disease; however, familial segregation information, in vitro functional studies, and additional clinical information were not included (PMID: 25174650); Reported previously in a patient with blindness; however, no further clinical information was provided and it is unclear if a second variant was present (PMID: 32483926); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32171587, 25174650, Kalia2023[preprint], 32483926) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 22, 2022	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia 11 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1707 of the SPG11 protein (p.Glu1707Asp). This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. This variant is present in population databases (rs145643238, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 406519). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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

Dec 08, 2022

The c.5121G>T variant (also known as p.E1707D), located in coding exon 29 of the SPG11 gene, results from a G to T substitution at nucleotide position 5121. The glutamic acid at codon 1707 is replaced by aspartic acid, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 29, which makes it likely to have some effect on normal mRNA splicing. The p.E1707D alteration was reported once in a cohort of 192 adult patients with neurodegenerative disorders in a patient with Parkinson's disease who also had a second alteration in the SPG11 gene, although phase of the alterations (cis vs. trans) was not determined (Ghani M, et al. Neurobiol Aging, 2015 Jan;36:545.e9-15). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is unavailable. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

SPG11-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2024

The SPG11 c.5121G>T variant is predicted to result in the amino acid substitution p.Glu1707Asp. This variant resides at the exon/intron boundary and is predicted to alter splicing based on prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant was reported in an individual with Parkinson disease (Table S2, Ghani et al. 2015. PubMed ID: 25174650) and in a large cohort of patients with inherited retinal and optical nerve disorders (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

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

-

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 15, 2023

Variant summary: SPG11 c.5121G>T (p.Glu1707Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon.Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 1559200 control chromosomes, predominantly at a frequency of 0.0019 within the Latino subpopulation in the gnomAD database, including 1 homozygotes (genomAD, v4). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.5121G>T has been reported in the literature in individuals affected with Parkinsons disease or blindness, without strong evidence for causality (example, Dineiro_2020, Ghani_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 25174650). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 02-03-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.6	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.94	P;.;P;.
Vest4		0.42
MutPred		0.32		Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);Loss of methylation at K1706 (P = 0.0778);
MVP		0.82
MPC		0.042
ClinPred		0.12	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145643238; hg19: chr15-44877834;