rs139334167

Positions:

Variant summary

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

The NM_025137.4(SPG11):c.7069C>T(p.Leu2357Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,770 control chromosomes in the GnomAD database, including 2 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 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 1.39

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=0.010218263).

BP6

Variant 15-44564629-G-A is Benign according to our data. Variant chr15-44564629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188332.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=3}. Variant chr15-44564629-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00145 (221/152252) while in subpopulation AMR AF= 0.00471 (72/15294). AF 95% confidence interval is 0.00383. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.7069C>T	p.Leu2357Phe	missense_variant	39/40	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.7069C>T	p.Leu2357Phe	missense_variant	39/40	1	NM_025137.4	ENSP00000261866		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

221

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00140

AC:

352

AN:

251112

Hom.:

AF XY:

0.00142

AC XY:

193

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00963

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00132

AC:

1924

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

960

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.00145

AC:

221

AN:

152252

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00199

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00131

AC:

159

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00245

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	This variant is associated with the following publications: (PMID: 25174650, 29525178) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SPG11: BS2 -

Hereditary spastic paraplegia 11

Uncertain:1Benign:1

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2021

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2023

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

Apr 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

0.95

D;D;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.053

T;D

Sift4G

Uncertain

0.055

T;T

Polyphen

1.0

D;.

Vest4

0.50

MVP

0.76

MPC

0.26

ClinPred

0.069

GERP RS

5.3

Varity_R

0.20

gMVP

0.37

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