rs111347025

Positions:

chr15-44615364-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_025137.4(SPG11):c.3037A>G(p.Lys1013Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,368 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0095 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 129 hom. )

Consequence

SPG11
NM_025137.4 missense, splice_region

Scores

Splicing: ADA: 0.5875

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 1.67

Variant links:

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]

SPG11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009679407).

BP6

Variant 15-44615364-T-C is Benign according to our data. Variant chr15-44615364-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194676.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=9}. Variant chr15-44615364-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00946 (1441/152346) while in subpopulation AMR AF= 0.0148 (227/15300). AF 95% confidence interval is 0.0133. There are 8 homozygotes in gnomad4. There are 716 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.3037A>G	p.Lys1013Glu	missense_variant, splice_region_variant	16/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.3037A>G	p.Lys1013Glu	missense_variant, splice_region_variant	16/40	1	NM_025137.4		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00946

AC:

1440

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0102

AC:

2564

AN:

251164

Hom.:

AF XY:

0.0107

AC XY:

1448

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00830

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0116

AC:

16941

AN:

1461022

Hom.:

129

Cov.:

AF XY:

0.0118

AC XY:

8553

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.0115

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00818

Gnomad4 FIN exome

AF:

0.00139

Gnomad4 NFE exome

AF:

0.0130

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00946

AC:

1441

AN:

152346

Hom.:

Cov.:

AF XY:

0.00961

AC XY:

716

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.0134

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0139

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.00992

AC:

1205

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0178

EpiControl

AF:

0.0169

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 11

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 08, 2018	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 16, 2017	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Lys1013Glu variant in SPG11 has been identified in 2 individuals with spastic paraplegia and no other variant identified in the gene (PMID: 23733235), but has also been identified in >1% of European (non-Finnish) chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for spastic paraplegia. -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 03, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Amyotrophic lateral sclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Sep 09, 2020

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 12, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

SPG11: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

T;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.082

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.72

T;T;T;T

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.2

L;L;.;L

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.46

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.44

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0020

B;.;B;.

Vest4

0.25

MPC

0.047

ClinPred

0.0030

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over