15-44651599-T-C

Position:

chr15-44651599-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.354

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 -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	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.1348A>G	p.Ile450Val	missense_variant	6/40	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.1348A>G	p.Ile450Val	missense_variant	6/40	1	NM_025137.4	ENSP00000261866.7		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2226

AN:

152162

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0110

AC XY:

7996

AN XY:

727244

show subpopulations

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.:

Cov.:

AF XY:

0.0176

AC XY:

1314

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.00419

AC:

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Hereditary spastic paraplegia 11

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
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	Athena Diagnostics	May 15, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 14, 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

0.078

BayesDel_addAF

Benign

-0.59

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

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.;L;.

PrimateAI

Benign

0.30

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

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

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