rs200573434

Positions:

chr15-44663632-C-T

Variant summary

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

The NM_025137.4(SPG11):c.16G>A(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,595,546 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 0.341

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:

SPG11 (HGNC:):

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=0.0047059953).

BP6

Variant 15-44663632-C-T is Benign according to our data. Variant chr15-44663632-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216771.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5, Benign=2}. Variant chr15-44663632-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00138 (210/152370) while in subpopulation NFE AF= 0.00215 (146/68030). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.16G>A	p.Gly6Arg	missense_variant	1/40	ENST00000261866.12	NP_079413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.16G>A	p.Gly6Arg	missense_variant	1/40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00129

AC:

276

AN:

214166

Hom.:

AF XY:

0.00126

AC XY:

150

AN XY:

119160

show subpopulations

Gnomad AFR exome

AF:

0.000827

Gnomad AMR exome

AF:

0.000701

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.0000587

Gnomad SAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00109

GnomAD4 exome

AF:

0.00213

AC:

3075

AN:

1443176

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1501

AN XY:

717648

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.000687

Gnomad4 ASJ exome

AF:

0.0000776

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.000141

Gnomad4 FIN exome

AF:

0.000742

Gnomad4 NFE exome

AF:

0.00257

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152370

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00215

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00153

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00131

AC:

ExAC

AF:

0.00138

AC:

166

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2021	This variant is associated with the following publications: (PMID: 18337587) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SPG11: BP4, BS2 -

Hereditary spastic paraplegia 11

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Amyotrophic lateral sclerosis type 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 28, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2020

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

9.7

DANN

Benign

0.96

DEOGEN2

Benign

0.010

T;.;T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.61

T;T;T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.4

L;L;.;L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.64

N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.22

T;T;T;T;T

Sift4G

Benign

0.074

T;T;T;D;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.17

MutPred

0.32

Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);Gain of MoRF binding (P = 0.0266);

MVP

0.67

MPC

0.041

ClinPred

0.0068

GERP RS

2.5

Varity_R

0.036

gMVP

0.23

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

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