rs199765540

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_025137.4(SPG11):c.1126A>G(p.Asn376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,614,070 control chromosomes in the GnomAD database, including 1 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

SPG11
NM_025137.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.408

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04661444).

BP6

Variant 15-44651821-T-C is Benign according to our data. Variant chr15-44651821-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387116.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPG11	NM_025137.4 linkuse as main transcript	c.1126A>G	p.Asn376Asp	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.1126A>G	p.Asn376Asp	missense_variant	6/40	1	NM_025137.4		Q96JI7-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251086

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000980

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000112

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2021

The p.N376D variant (also known as c.1126A>G), located in coding exon 6 of the SPG11 gene, results from an A to G substitution at nucleotide position 1126. The asparagine at codon 376 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 376 of the SPG11 protein (p.Asn376Asp). This variant is present in population databases (rs199765540, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 387116). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.60

Cadd

Benign

6.0

Dann

Benign

0.84

DEOGEN2

Benign

0.0084

T;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.047

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.39

N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.70

T;T;T;T;T

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

0.0010

B;.;B;.;.

Vest4

0.033

MVP

0.48

MPC

0.047

ClinPred

0.013

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.15

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