rs3759873

chr15-44651599-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025137.4(SPG11):c.1348A>G(p.Ile450Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,166 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (60 hom., cov: 32)
  • Exomes 𝑓: 0.010 (308 hom.)
• Consequence: SPG11 NM_025137.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.354

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001638025).
• BP6: Variant 15-44651599-T-C is Benign according to our data. Variant chr15-44651599-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44651599-T-C is described in Lovd as [Benign]. Variant chr15-44651599-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.1348A>G	p.Ile450Val	missense_variant	6/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.1348A>G	p.Ile450Val	missense_variant	6/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2226 AN: 152162 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0187 AC: 4695 AN: 251442 Hom.: 135 AF XY: 0.0188 AC XY: 2555 AN XY: 135900

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0965

Gnomad SAS exome AF: 0.0370

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0103 AC: 15023 AN: 1461886 Hom.: 308 Cov.: 35 AF XY: 0.0110 AC XY: 7996 AN XY: 727244

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00662

Gnomad4 EAS exome AF: 0.0753

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0147 AC: 2241 AN: 152280 Hom.: 60 Cov.: 32 AF XY: 0.0176 AC XY: 1314 AN XY: 74458

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0998

Gnomad4 SAS AF: 0.0487

Gnomad4 FIN AF: 0.0354

Gnomad4 NFE AF: 0.00544

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00478 Hom.: 2

Bravo AF: 0.0129

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.0187 AC: 2273

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary spastic paraplegia 11 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 14, 2021

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

Amyotrophic lateral sclerosis type 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.3
Dann	Benign	0.27
DEOGEN2	Benign	0.014	T;.;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.;L;.
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.050	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.74	T;T;T;T;T
Sift4G	Benign	0.86	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.065
MPC		0.033
ClinPred		0.0027	T
GERP RS		1.4
Varity_R		0.012
gMVP		0.16

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: rs3759873; hg19: chr15-44943797; COSMIC: COSV55998743;