rs150761878

chr15-44572768-C-Achr15-44572768-C-Gchr15-44572768-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025137.4(SPG11):c.6258G>T(p.Leu2086=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,614,044 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (48 hom.)
• Consequence: SPG11 NM_025137.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -0.0190

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-44572768-C-A is Benign according to our data. Variant chr15-44572768-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130366.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=4}. Variant chr15-44572768-C-A is described in Lovd as [Likely_benign]. Variant chr15-44572768-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00517 (787/152216) while in subpopulation NFE AF= 0.00604 (411/68016). AF 95% confidence interval is 0.00556. There are 6 homozygotes in gnomad4. There are 444 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4	c.6258G>T	p.Leu2086=	synonymous_variant	33/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12	c.6258G>T	p.Leu2086=	synonymous_variant	33/40	1	NM_025137.4

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 152098 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00656 AC: 1650 AN: 251484 Hom.: 16 AF XY: 0.00633 AC XY: 861 AN XY: 135916

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00587 AC: 8578 AN: 1461828 Hom.: 48 Cov.: 32 AF XY: 0.00563 AC XY: 4093 AN XY: 727224

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.00581

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152216 Hom.: 6 Cov.: 31 AF XY: 0.00597 AC XY: 444 AN XY: 74416

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0234

Gnomad4 NFE AF: 0.00604

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00451 Hom.: 2

Bravo AF: 0.00369

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 11 Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 04, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SPG11: BP4, BP7, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2014	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2017

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SPG11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	5.4
Dann	Benign	0.63

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: rs150761878; hg19: chr15-44864966; COSMIC: COSV99969966; COSMIC: COSV99969966;