rs77697105

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_025137.4(SPG11):c.1108G>A(p.Glu370Lys) variant causes a missense change. The variant allele was found at a frequency of 0.018 in 1,613,924 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.018 ( 311 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.68

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067484677).

BP6

Variant 15-44651839-C-T is Benign according to our data. Variant chr15-44651839-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44651839-C-T is described in Lovd as [Benign]. Variant chr15-44651839-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0163 (2483/152252) while in subpopulation NFE AF= 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 33 homozygotes in gnomad4. There are 1251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.1108G>A	p.Glu370Lys	missense_variant	6/40	ENST00000261866.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPG11	ENST00000261866.12 linkuse as main transcript	c.1108G>A	p.Glu370Lys	missense_variant	6/40	1	NM_025137.4		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2483

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00943

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0171

AC:

4280

AN:

250764

Hom.:

AF XY:

0.0174

AC XY:

2354

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00589

Gnomad FIN exome

AF:

0.0445

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0182

AC:

26581

AN:

1461672

Hom.:

311

Cov.:

AF XY:

0.0183

AC XY:

13321

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.00801

Gnomad4 ASJ exome

AF:

0.0239

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00667

Gnomad4 FIN exome

AF:

0.0435

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0163

AC:

2483

AN:

152252

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1251

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00363

Gnomad4 AMR

AF:

0.00942

Gnomad4 ASJ

AF:

0.0204

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0229

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0199

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.0204

AC:

175

ExAC

AF:

0.0167

AC:

2022

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 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	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 11

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 15, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SPG11: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 30, 2021

- -

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

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

0.0067

T;T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

M;M;.;M;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.029

D;D;D;D;D

Sift4G

Benign

0.31

T;T;T;D;D

Polyphen

0.38

B;.;B;.;.

Vest4

0.35

MPC

0.27

ClinPred

0.016

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.35

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